Articles de revues : « Acute Lymphoblastic Leukemia, children, IKAROS, miRNA »

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Vasquez, Marina Lipkin, Stefano Volinia, Cecilia Fernandez, Nicola Zanesi, Grazia Fazio, Ilana Renault Zalcberg, Ramiro Garzon, Giovanni Cazzaniga, Andrea Biondi et Carlo M. Croce. « Multivariate Analysis Reveals a miRNA Profile Correlated To Karyotype and Outcome In Pediatric B-Cell Precursor ALL ». Blood 122, n^o 21 (15 novembre 2013) : 2597. http://dx.doi.org/10.1182/blood.v122.21.2597.2597.

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Abstract Acute lymphoblastic leukemia (ALL) is the commonest childhood cancer and is characterized by the presence of recurring structural genetic alterations that have been associated to clinical response.Recently it has been shown that the deregulation of microRNAs (miRNA), a class of small RNAs that negatively control gene expression, is a common characteristic of hematological malignancies and may be related to the pathogenesis of leukemias. The aim of the current study was to explore which microRNAs are expressed by each subtype of pediatric B-cell precursor ALL and to determine their roles into clinical outcome. We analyzed samples from 94 children diagnosed as B-cell precursor ALL in Italy between 2000 and 2010 that were included in the AIEOP-BFM protocol of treatment. The patients were divided by cytogenetic subgroups of ALL. Cells CD34+ and CD19+ from healthy donors were used as negative controls. The miRNA signature was studied using microchips for miRNA microarray. We first performed a two-class comparison of miRNA expression between leukemic and non-leukemic samples and found 84 miRNAs differently expressed (P<0.01). A multivariate analysis of karyotype showed that 59 of these miRNAs were correlated to leukemia (P<0.01). All major subtypes of precursor B-cell ALL were analyzed: MLL-rearranged (10), TEL-AML1(15), E2A-PBX1(10), BCR-ABL(23), hyperdiploid(17), ‘normal Karyotype’ (19, defined as those not carrying the foregoing cytogenetic aberrations), and also the presence of IKAROS deletions was evaluated. Each subgroup was found to have unique microRNA-signature that differed from each other and from those of healthy hematopoietic cells. Both Kaplan Meier and Cox regression tests were performed to check how many of these miRNAs were correlated to clinic response, based on the induction failure, relapse, and survival. A multivariate analysis revealed that genetic subtypes and poor-responders patients display characteristic miRNA signatures. Specifically the mir-125b, 16-2, 24, 28-5p, 128a, 138-1 and 658 (all P<0.01) came out as independent prognostic factors predictive of event-free survival (EFS). IKAROS deletions did not come out as an independent prognostic factor, probably for being already associated to Ph+ and “BCR-ABL like” patients, who already have a poor prognosis. In addition, our group has previously shown that miR-125b may act as an oncogene and is correlated to a poor response in Ph+ samples, also increasing therapy resistance and leukemia aggressiveness in vivo. Further functional studies are needed to better explain the role of these miRNA and to provide new insights into the biology of pediatric ALL. Disclosures: Garzon: Karyopharm : Research Funding.

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Vasquez, Marina Lipkin, Nicola Zanesi, Stefano Volinia, Ramiro Garzon, Giovanni Cazzaniga, Carlo M. Croce et Andrea Biondi. « MiR-125b Cooperates with BCR-ABL and Enhances Therapy Resistance in Childhood Ph+ ALL ». Blood 118, n^o 21 (18 novembre 2011) : 78. http://dx.doi.org/10.1182/blood.v118.21.78.78.

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Abstract Abstract 78 The treatment improvements in the past two decades led childhood acute lymphoblastic leukemia (ALL) cure rates reach over 80%, but children who carry the Philadelphia (Ph+) chromosome still have high risk of relapse due to therapy resistance. Different results with large series of patients have shown that an earlier remission after induction with glucocorticoids and intrathecal methotrexate is correlated to a better outcome. Besides, the minimal residual disease (MRD) risk measured after induction is also correlated to the therapy response, indicating that an early response can predict Ph+ ALL overall outcome. Several studies have shown that Ph+ ALL is heterogeneous in terms of clinical parameters even if all patients carry BCR-ABL and most of them carry the oncogenic isoform of IKAROS. They respond differently to the treatment, which suggests the presence of additional mechanisms involved in leukemogenesis. In an attempt to find secondary genetic abnormalities that may be responsible for the Ph+ ALL chemo resistance and heterogeneity, we studied the miRNA expression profile in two patient groups discriminated by the initial therapy response. We included samples from 78 consecutive Ph+ ALL children diagnosed in Italy between 2000 and 2010. The miRNA signature was analyzed by miRNA array using Applied Biosystems Array-Cards comparing two patient groups differentiated according to MRD and prednisone response. A particular miRNA profile was found in the poor responder group and it was confirmed using specific miRNA single assays from AB. Specially the miR-125b was up to ten-fold overexpressed compared to the good responder group (p =.006). To investigate the functional role of miR-125b in Ph+ ALL we used BCR-ABL positive cell lines (3 ALL and one CML in blast-crisis) to create a xenograft leukemia model and induced miRNA upregulation by direct inoculation of synthetic miR-125b (premiR). Tumors injected with premiR-125b (n=14) were significantly bigger than the scrambled oligonucleotide (n=10) and mock controls (n=4) (p=.04). After two weeks the premiR-125b tumors grew six-fold more than controls and average tumor weights for the scrambled oligonucleotides and the premiR-125b inoculated mice were 0.63 g and 1.56 g, respectively (p =.01). Further, we determined whether miR-125b protects the tumor cells from apoptosis after treatment with Dexamethasone. While tumors injected with scrambled molecules were 70% reduced after 10 days of corticoid treatment, tumors injected with premiR-125b were only 30% reduced (p=.05). Together, these results suggest that miR-125b acts as an oncogene in Ph+ ALL and its overexpression accelerates the role of BCR-ABL, increasing therapy resistance and leukemia aggressiveness. Additional studies will be necessary to understand why this miRNA is overexpressed in some patients and how it acts in cooperation with BCR-ABL to induce leukemia. In the future, novel therapies using miRNAs as targets can emerge as strategies to be added to the anti-tyrosine kinase drugs in order to improve treatment response and survivor in Ph+ ALL. Disclosures: No relevant conflicts of interest to declare.

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Kogut, Sophie, Hana Paculova, Princess Rodriguez, Joseph Boyd, Alyssa Richman, Amrita Palaria, Hilde Schjerven et Seth Frietze. « Ikaros Regulates microRNA Networks in Acute Lymphoblastic Leukemia ». Epigenomes 6, n^o 4 (19 octobre 2022) : 37. http://dx.doi.org/10.3390/epigenomes6040037.

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The hematopoietic transcription factor Ikaros (IKZF1) regulates normal B cell development and functions as a tumor suppressor in precursor B cell acute lymphoblastic leukemia (B-ALL). MicroRNAs (miRNAs) are small regulatory RNAs that through post-transcriptional gene regulation play critical roles in intracellular processes including cell growth in cancer. However, the role of Ikaros in the regulation of miRNA expression in developing B cells is unknown. In this study, we examined the Ikaros-regulated miRNA targets using human IKZF1-mutated Ph+ B-ALL cell lines. Inducible expression of wild-type Ikaros (the Ik1 isoform) caused B-ALL growth arrest and exit from the cell cycle. Global miRNA expression analysis revealed a total of 31 miRNAs regulated by IK1, and ChIP-seq analysis showed that Ikaros bound to several Ik1-responsive miRNA genes. Examination of the prognostic significance of miRNA expression in B-ALL indicate that the IK1-regulated miRNAs hsa-miR-26b, hsa-miR-130b and hsa-miR-4649 are significantly associated with outcome in B-ALL. Our findings establish a potential regulatory circuit between the tumor-suppressor Ikaros and the oncogenic miRNA networks in IKZF1-mutated B-ALL. These results indicate that Ikaros regulates the expression of a subset of miRNAs, of which several may contribute to B-ALL growth.

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Sun, Lei, Patricia A. Goodman, Carla M. Wood, Mya-Lisa Crotty, Martha Sensel, Harland Sather, Christopher Navara et al. « Expression of Aberrantly Spliced Oncogenic Ikaros Isoforms in Childhood Acute Lymphoblastic Leukemia ». Journal of Clinical Oncology 17, n^o 12 (décembre 1999) : 3753–66. http://dx.doi.org/10.1200/jco.1999.17.12.3753.

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PURPOSE: We sought to determine if molecular abnormalities involving the Ikaros gene could contribute to the development of acute lymphoblastic leukemia (ALL) in children. PATIENTS AND METHODS: We studied Ikaros gene expression in normal human bone marrow, normal thymocytes, normal fetal liver–derived immature lymphocyte precursor cell lines, eight different ALL cell lines, and leukemic cells from 69 children with ALL (T-lineage ALL, n = 18; B-lineage ALL, n = 51). Expression of Ikaros protein and its subcellular localization were examined by immunoblotting and confocal laser-scanning microscopy, respectively. Polymerase chain reaction (PCR) and nucleotide sequencing were used to identify the specific Ikaros isoforms expressed in these cells. Genomic sequencing of splice junction regions of the Ikaros gene was performed in search for mutations. RESULTS: In each of the ALL cases, we found high-level expression of a non–DNA-binding or aberrant DNA-binding isoform of Ikaros with abnormal subcellular compartmentalization patterns. In contrast, only wild-type Ik-1 and Ik-2 isoforms with normal subcellular localization were found in normal bone marrow cells and thymus-derived or fetal liver–derived normal lymphocyte precursors. In leukemic cells expressing the aberrant Ikaros coding sequences with the 30-base-pair deletion, genomic sequence analysis of the intron-exon junctions between exons 6 and 7 yielded the wild-type sequence. We identified a single nucleotide polymorphism (SNP) affecting the third base of the triplet codon for a proline (CCC or CCA) in the highly conserved bipartite activation region (viz, A or C at position 1002 numbering from the translation start site of Ik-1) within our Ikaros clones. Bi-allelic expression of truncated and/or non–DNA-binding isoforms along with wild-type isoforms was observed in leukemic cells, which implicates trans-acting factor(s) affecting splice site recognition. CONCLUSION: Our findings link specific molecular defects involving the Ikaros gene to childhood ALL. Posttranscriptional regulation of alternative splicing of Ikaros RNA seems to be defective in leukemic lymphocyte precursors from most children with ALL. Consequently, leukemic cells from ALL patients, in contrast to normal lymphocyte precursors, express high levels of non–DNA-binding Ikaros isoforms that are reminiscent of the non–DNA-binding Ikaros isoforms that lead to lymphoblastic leukemia in mice.

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Yang, Yung-Li, Sung-Liang Yu, Hsuan-Yu Chen, Pan-Chyr Yang, Jiann-Shiuh Chen, Dong-Tsamn Lin, Shu-Rung Lin et al. « MicroRNA Expression in Childhood Acute Lymphoblastic Leukemia (ALL) ». Blood 112, n^o 11 (16 novembre 2008) : 4467. http://dx.doi.org/10.1182/blood.v112.11.4467.4467.

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Abstract MicroRNAs (miRNAs) are small RNAs of 19 to 25 nucleotides that are regulators of gene expression. A role for microRNAs in leukemia, such as chronic lymphoblastic leukemia, acute myelogeneous leukemia has recently been recognized. However, little is known about the role of microRNAs in childhood acute lymphoblastic leukemia (ALL). To determine whether miRNAs are associated with the clinical features of childhood ALL and its association with cytogenetic abnormalities, we analyzed 60 untreated childhood ALL cases for their miRNA expression using a microarray platform. Leukemic samples were collected from the ALL children between 1–18 years of age. Of the 365 miRNA analyzed with a training group of 40 patients, a miRNA signature was derived that was associated with event-free survival. The signature was tested in a validation group of 20 patients. For the latter, a miRNA compound covariate predictor (i.e., a miRNA risk score) was computed on the basis of weighted levels of the miRNAs forming the outcome signature. The signature identified from the training group contained 5 miRNA highly associated with event-free survival (P<0.05). The summary value of the signature miRNA was also highly associated with event-free survival (P <0.05) in the validation group. After adjustment for the gender, age, initial white counts, immunophenotypes, and cytogenetics, the miRNA risk score remained associated with event-free survival (P <0.05) in multivariable analysis. In conclusion, we have identified a miRNA signature of 5 miRNAs which is highly associated with the clinical outcome, cytogenetic and immunophenotypic subtypes of childhood ALL.

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Ge, Zheng, Chunhua Song, Yali Ding, Bi-Hua Tan, Dhimant Desai, Arati Sharma, Raghavendra Gowda et al. « Dual targeting of MTOR as a novel therapeutic approach for high-risk B-cell acute lymphoblastic leukemia ». Leukemia 35, n^o 5 (2 février 2021) : 1267–78. http://dx.doi.org/10.1038/s41375-021-01132-5.

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AbstractChildren of Hispanic/Latino ancestry have increased incidence of high-risk B-cell acute lymphoblastic leukemia (HR B-ALL) with poor prognosis. This leukemia is characterized by a single-copy deletion of the IKZF1 (IKAROS) tumor suppressor and increased activation of the PI3K/AKT/mTOR pathway. This identifies mTOR as an attractive therapeutic target in HR B-ALL. Here, we report that IKAROS represses MTOR transcription and IKAROS’ ability to repress MTOR in leukemia is impaired by oncogenic CK2 kinase. Treatment with the CK2 inhibitor, CX-4945, enhances IKAROS activity as a repressor of MTOR, resulting in reduced expression of MTOR in HR B-ALL. Thus, we designed a novel therapeutic approach that implements dual targeting of mTOR: direct inhibition of the mTOR protein (with rapamycin), in combination with IKAROS-mediated transcriptional repression of the MTOR gene (using the CK2 inhibitor, CX-4945). Combination treatment with rapamycin and CX-4945 shows synergistic therapeutic effects in vitro and in patient-derived xenografts from Hispanic/Latino children with HR B-ALL. These data suggest that such therapy has the potential to reduce the health disparity in HR B-ALL among Hispanic/Latino children. The dual targeting of oncogene transcription, combined with inhibition of the corresponding oncoprotein provides a paradigm for a novel precision medicine approach for treating hematological malignancies.

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Zhou, Fen, Heng Mei, Runming Jin, Xiaoqing Li et Xiangjun Chen. « Expression of Ikaros Isoform 6 in Chinese Children With Acute Lymphoblastic Leukemia ». Journal of Pediatric Hematology/Oncology 33, n^o 6 (août 2011) : 429–32. http://dx.doi.org/10.1097/mph.0b013e318217f5f2.

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Dovat, Sinisa, Yali Ding, Dhimant Desai et Arati Sharma. « Abstract A088 : Targeting endoplasmic reticulum stress-induced apoptosis to reduce health disparity in high-risk B-cell acute lymphoblastic leukemia in Hispanic/Latino children ». Cancer Epidemiology, Biomarkers & ; Prevention 32, n^o 1_Supplement (1 janvier 2023) : A088. http://dx.doi.org/10.1158/1538-7755.disp22-a088.

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Abstract B-cell Acute Lymphoblastic Leukemia (ALL) is the most common childhood malignancy. The death rate from B-ALL in Hispanic/Latino (H/L) is 40% higher than in non-Hispanic whites (NHW) after correcting socioeconomic factors. Deletion of one IKZF1 allele is highly increased H/L children, which provides a biological rationale for the worse prognosis of B-ALL in this population. The very high incidence (31% in all children and 65% in children ≥10 yrs) makes the deletion of one IKZF1 allele the most frequent genetic alteration that confers adverse prognosis in B-ALL in H/L children. The IKZF1 gene encodes a DNA-binding protein, IKAROS, which functions as a transcriptional regulator. Identification of IKAROS target genes in B-ALL of H/L children is essential to understand the specificity of B-ALL pathogenesis in those children and develop the targeted treatment to reduce the health disparity in survival for H/L children with B-ALL. Global DNA-binding analysis of primary B-ALL cells from H/L children showed that IKAROS binds to the promoter of eukaryotic elongation factor 2 kinase (eEF2K). eEF2K regulates protein synthesis, cell cycle progression and malignant transformation. The activity of eEF2K is increased in human malignancies, including B-ALL, and eEF2K is a critical regulator of endoplasmic reticulum (ER) stress-induced autophagy and apoptosis in tumor cells. The role of IKAROS in the regulation of eEF2K expression in B-ALL of H/L children was established using gain-of-function and loss-of-function experiments. Overexpression of IKZF1 in H/L B-ALL cells results in reduced expression of eEF2K, while IKZF1 knock-down results in increased transcription of eEF2K in H/L B-ALL. Since IKAROS function in leukemia is regulated by pro-oncogenic Casein Kinase 2 (CK2), we tested whether CK2 can control the ability of IKAROS to regulate the expression of eEF2K in H/L B-ALL. Increased expression of CK2 in H/L B-ALL results in increased expression of the eEF2K gene due to the loss of IKAROS binding to the promoter of the eEF2K genes. Inhibition of CK2 with shRNA and/or a specific CK2 inhibitor, CX-4945, restores IKAROS binding to promoter of eEF2K in high-risk B-ALL with deletion of one IKZF1 allele in H/L children. Restoration of IKAROS binding to promoter of eEF2K in high-risk B-ALL in H/L children results in reduced expression of this gene. This was associated with increased sensitivity to Akt inhibition by MK-2206. Combination treatment with CK2 inhibitor and MK-2206 showed a synergistic effect on B-ALL cells from H/L children. In summary, presented data demonstrate that IKAROS and CK2 regulate ER stress-induced apoptosis via regulation of eEF2K expression in high-risk B-ALL in Hispanic/Latino children. Results suggest that targeting ER stress-induced apoptosis in combination with CK2 inhibitors can be an efficient treatment to reduce the health disparity in survival for Hispanic/Latino children with B-ALL. Citation Format: Sinisa Dovat, Yali Ding, Dhimant Desai, Arati Sharma. Targeting endoplasmic reticulum stress-induced apoptosis to reduce health disparity in high-risk B-cell acute lymphoblastic leukemia in Hispanic/Latino children [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr A088.

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Gutierrez-Camino, Angela, Susana Garcia-Obregon, Elixabet Lopez-Lopez, Itziar Astigarraga et Africa Garcia-Orad. « miRNA deregulation in childhood acute lymphoblastic leukemia : a systematic review ». Epigenomics 12, n^o 1 (janvier 2020) : 69–80. http://dx.doi.org/10.2217/epi-2019-0154.

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Despite remarkable improvements in survival of childhood acute lymphoblastic leukemia (ALL), nonresponding or relapsing patients still represent one of the most frequent causes of death by disease in children. Accurate patient risk stratification based on genetic markers could increases survival rates. miRNAs can represent novel candidates with diagnostic, predictive and prognostic potential; however, many groups investigated their involvement with contradictory results. Aim: To clarify the role of miRNAs as biomarkers through a systematic review. Results: From a revision of 45 manuscripts, we found that miR-128 and miR-181 overexpression could represent markers for ALL diagnosis and underexpression of miR-708 and miR-99a could be markers for bad prognosis. Conclusion: These signatures could refine classification and risk stratification of patients and improve ALL outcome.

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Veer, Arian Van Der, Marieke E. Willemse, Valerie De Haas, Anjo J. P. Veerman, Willem A. Kamps, Rob Pieters et Monique L. Den Boer. « Unfavorable Prognostic Value of IKAROS but Not CRLF2 in Children with BCRABL1-positive Acute Lymphoblastic Leukemia »,. Blood 118, n^o 21 (18 novembre 2011) : 3528. http://dx.doi.org/10.1182/blood.v118.21.3528.3528.

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Abstract Abstract 3528 Despite the relative high success-rate to treat children (<18 yrs) with precursor B-ALL (5-year event-free survival >80%), the prognosis of the subtype of BCRABL1- positive ALL remains poor (5-year event-free survival <50%). Patients carrying this translocation are treated according to intensified high-risk protocols which are, however, associated with therapy-related side-effects and mortality. A different treatment for those cases at high risk of treatment failure and less treatment for those at low risk of treatment failure is preferred to improve overall outcome results in children with BCRABL1 -positive ALL. Deletions in the gene encoding Ikaros (IKZF1) and an aberrant high expression level of the cytokine receptor-like factor 2 gene (CRLF2) have both recently been associated with a poor prognosis of children with newly diagnosed precursor B-ALL. We here studied whether these genomic abnormalities can also serve as prognostic factor within the subset of BCRABL1 -positive pediatric ALL. Methods; Leukemic cells of BCRABL1- positive patients enrolled in two consecutive treatment protocols of the Dutch Childhood Oncology Group (DCOG) were analyzed for IKZF1 and CRLF2 status. IKZF1 deletions were determined by Multiplex Ligation Probe-based Amplification assays (MLPA) and comparative genomic hybridization arrays (aCGH; Agilent, Sureprint G3 Human CG 180K). The p335 MPLA assay (MRC Holland) was used for discovery of IKZF1 deletions and data were validated by aCGH and a second MLPA assay (p202; MRC Holland) with higher resolution for affected regions. CRLF2 expression levels were determined by Affymetrix U133 plus 2.0 gene expression arrays. A large cohort of 459 newly diagnosed ALL cases served as reference. A high level of CRLF2 expression was assigned to 10% of all cases ranked according to CRLF2 expression level. Results; Deletions in IKZF1 were found in 65% of the cases (n=11); 10 cases had a partial deletion between exon 2 and 7 of IKZF1 resulting in a dominant negative variant and 1 case had a deletion of the complete IKZF1 gene. Analysis of patient characteristics revealed that cases with deletions in IKZF1 have a median 4.5-fold higher white blood cell count compared to unaffected cases (p=0.009). Analysis of the cumulative incidence of relapse (pCIR) with death as a competing risk indicated that children with IKZF1 -deleted BCRABL1 -positive ALL had a significantly increased risk of developing a relapse compared with those with an unaffected IKZF1 gene (73% versus 17%, p=0.02). As a consequence, the 5-year event-free survival was also lower for the IKZF1- deleted group compared to the unaffected group (18% versus 67% p=0.04, Log-Rank). The expression level of CRLF2 in BCRABL1- positive cases was median 91.4 arbitrary units (p25-p75: 84.2–97.2) compared to 91.3 arbitrary units (p25-p75: 82.6–107.3) for BCRABL1 -negative cases (p>0.05). Expression of none of the BCRABL1 -positive ALL cases was ranked within the highest 10% percentile of the reference group. Hence, high expression of CRLF2 cannot explain a poor prognosis of BCRABL1- positive cases. In conclusion, our data show that a deletion of IKZF1 but not a high expression of CRLF2 is a strong discriminative prognostic factor in BCRABL1- positive pediatric precursor B-ALL. We therefore advocate to implement the IKZF1 status as a new prognostic factor in BCRABL1- positive pediatric ALL. Disclosures: No relevant conflicts of interest to declare.

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Duyu, Muhterem, Burak Durmaz, Cumhur Gunduz, Canan Vergin, Deniz Yilmaz Karapinar, Serap Aksoylar, Kaan Kavakli et al. « Prospective Evaluation of Whole Genome MicroRNA Expression Profiling in Childhood Acute Lymphoblastic Leukemia ». BioMed Research International 2014 (2014) : 1–7. http://dx.doi.org/10.1155/2014/967585.

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Dysregulation of microRNA (miRNA) expression contributes to the pathogenesis of several clinical conditions. The aim of this study is to evaluate the associations between miRNAs and childhood acute lymphoblastic leukemia (ALL) to discover their role in the course of the disease. Forty-three children with ALL and 14 age-matched healthy controls were included in the study. MicroRNA microarray expression profiling was used for peripheral blood and bone marrow samples. Aberrant miRNA expressions associated with the diagnosis and outcome were prospectively evaluated. Confirmation analysis was performed by real time RT-PCR. miR-128, miR-146a, miR-155, miR-181a, and miR-195 were significantly dysregulated in ALL patients at day 0. Following a six-month treatment period, the change in miRNA levels was determined by real time RT-PCR and expression of miR-146a, miR-155, miR-181a, and miR-195 significantly decreased. To conclude, these miRNAs not only may be used as biomarkers in diagnosis of ALL and monitoring the disease but also provide new insights into the potential roles of them in leukemogenesis.

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A Gobran M. Sc, Eman, Ghada NasrM Nasr PhD, Mohamed Y Nasr PhD et Mahmoud I Nasr PhD. « MicroRNAs : new biomarker for diagnosis, prognosis, therapy prediction and therapeutic tools for acute lymphoblastic leukemia ». International Journal of Biological Research 7, n^o 1 (31 juillet 2019) : 1. http://dx.doi.org/10.14419/ijbr.v7i1.29429.

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Back ground: MicroRNA (miRNA) was originally discovered in Caenorhabditis elegans by Victor Ambrose in 1993. It was predicted that miRNA account for 1-6% of the human genome and regulated at least 33% of protein-coding genes. Recently, 945 distinct miRNAs molecules have been identified within the human genome. It has been associated with the pathogenesis, progression and prognosis of different diseases, such as leukemia. MiR-181 family is one of those miRNA families, which generally expressed in 70 species and various human cancers.Objective: Assessment of mir-181a and LDH as promising co-biomarkers in order to provide additional information influence decisions about treatment sequentially to improve health outcomes of ALL in the Egyptian children.Patients and methods: This study was conducted on 100 children; 50 with ALL (38 males and 12 females) as ALL group. Other 50 healthy age and sex matched children were collected randomly as control group. Serum lactate dehydrogenase (LDH) and miRNA-181a were evaluated for all participants.Results: The results showed that there was a statistical significant difference between ALL and control groups regarding both molecular and biochemical indications of mir-181a and LDH were about almost five time as the control value, (P = 0.001). The ROC curve analysis revealed that the studied LDH and mir-181a markers were highly sensitive, highly specific and highly accurate test in the differentiation between the two studied ALL and control groups, with cutoff: ALL if mir-181a > 2.071, ALL if LDH > 0.307 respectively.Conclusion: MiRNA-181a and LDH can be used as co-biomarkers for ALL and might be beneficial in early diagnosis.

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Jemimah Devanandan, Helen, Vettriselvi Venkatesan, Julius Xavier Scott, Latha Sneha Magatha, Solomon Franklin Durairaj Paul et Teena Koshy. « MicroRNA 146a Polymorphisms and Expression in Indian Children with Acute Lymphoblastic Leukemia ». Laboratory Medicine 50, n^o 3 (21 décembre 2018) : 249–53. http://dx.doi.org/10.1093/labmed/lmy074.

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Abstract Background MicroRNAs (miR) have been reported to be involved in hematopoiesis and in the pathogenesis of several hematological malignant neoplasms. Single-nucleotide polymorphisms (SNPs) in human miR genes may alter the expression of those genes and influence the predisposition to childhood leukemia. Objective To evaluate the association of rs2910164 G>C, rs57095329 A>G and the expression of miRNA-146a in ethnic South Asian children with acute lymphoblastic leukemia (ALL). Method Genotyping and expression analysis using TaqMan Small RNA Assay was performed on 71 patients with pathologically confirmed ALL and 74 control individuals. Results No statistically significant association was found between the 2 SNPs, its expression levels, and ALL risk. Conclusion Haplotype analysis indicated a combination of allele A of rs57095329 and allele G of rs2910164 could represent a risk haplotype and an allele combination of G of rs57095329 and G of rs2910164 could represent a protective haplotype for ALL.

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Volejnikova, Jana, Ester Mejstrikova, Jan Stary, Jan Trka et Eva Fronkova. « Relative Expression of Ikaros Isoforms Has a Prognostic Impact in Phildelphia-Negative Childhood Acute Lymphoblastic Leukemia. » Blood 114, n^o 22 (20 novembre 2009) : 1282. http://dx.doi.org/10.1182/blood.v114.22.1282.1282.

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Abstract Abstract 1282 Poster Board I-304 Ikaros, encoded by the IKZF1 gene, is a zinc-finger transcription factor crucial for normal differentiation of the lymphoid lineage. Multiple isoforms of Ikaros are generated by alternative splicing in lymphoid progenitors. Recent studies based primarily on high-risk (HR) patients with ALL, including Philadelphia-positive cases, have shown an inferior prognosis of patients with Ikaros alterations, leading in most cases to the expression of short, non-DNA binding isoforms of IKZF1. There is only a limited information about the overall frequency and prognostic impact of IKZF1 alterations in non-selected, BCR/ABL-negative ALL cohorts. Using a simplified yet efficient approach based on expression assay described by Iaccobucci et al. together with Agilent-on-chip semi-quantitative electrophoresis, we examined the expression of IKZF1 transcript variants in diagnostic bone marow (BM) samples from 94 children with Ph- ALL. The patients were diagnosed between November 2002 and December 2004 and treated by ALL IC-BFM 2002 protocol. Based on the analysis of peripheral blood from healthy donors and remission BM samples, we determined physiological range for relative expression of IKZF1 isoforms. The ratio between non-DNA binding (IK4, IK4del, IK4A, IK8) and functional IK1 and IK2 isoforms was significantly elevated in 26 of 94 patients (28%). There were no associations between elevated short/long isoforms ratio and age, WBC, ALL IC risk group, TEL/AML1 or hyperdiploidy. Considering the key role of Ikaros in lymphoid lineage specification, we tested whether its altered expression was related to the expression of myeloid markers on leukemic blasts. Neither short/long isoforms ratio, nor single transcript variant expression had any relation to the level of myeloperoxidase (MPO), CD13, CD33, CD65, CD117, CD14 or CD15 expression estimated by flow cytometry. Patients having the short/long isoforms ratio more than 80% had a 5-year RFS 66.7±13.6% compared to 87.5±4.1% in other patients (p=0.04). The main difference between leukemic and normal samples was observed in the relative expression of IK6 dominant-negative isoform. Using a cut-off of 10%, 14 of 94 (15%) ALL samples had increased IK6 expression in relation to other isoforms. Only 2 of 94 patients (2%) expressed IK6 alone. Elevated relative IK6 expression in the range 10-20% (6 patients) had no prognostic impact. Using a cut-off of 20%, 5-year RFS survival was 90.2± 3.3% in the group with low IK6 expression compared to 37.5±17.1% in patients with the high expression (p<0.0001). With the cut-off of 50%, RFS was 20±17.9% in the IK6 high expression group compared to 89.4±3.3% in the group with low expression (p<0.0001). Of the 5 patients with IK6 expression higher than 50%, two were treated in ALL IC HR group (based on poor prednisone response), one in the intermediate risk and two in the standard risk group, based on WBC, age and BM status at day 15. Only 1 of 4 patients with available MRD would be classified as MRD-HR based on MRD higher than 10−3 at week 12. Surprisingly, elevated relative expression of IK4, IK4del, IK4A and IK8 (all non-DNA binding isoforms) had no prognostic impact. The absolute level of IKZF1 expression, which might have indicated IKZF1 haploinsufficiency, had no prognostic impact either. In conclusion, we showed that a substantial proportion of childhood Ph-negative ALL cases had an increased expression of short, non-DNA binding Ikaros transcripts. However, only elevated expression of the IK6 isoform had prognostic impact. Patients with IK6 expression higher than 50% (5% of all patients) had very poor prognosis. The method used in this study could serve as a rapid screening for a new subgroup of HR patients with ALL. Supported by GA UK 7393/2007, MSMT NPV 2B06064, VZ MSM 0021620813 and MZ 000064203. Disclosures No relevant conflicts of interest to declare.

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Ghodousi, Elaheh Sadat, Narges Aberuyi et Soheila Rahgozar. « Simultaneous changes in expression levels of BAALC and miR-326 : a novel prognostic biomarker for childhood ALL ». Japanese Journal of Clinical Oncology 50, n^o 6 (4 mars 2020) : 671–78. http://dx.doi.org/10.1093/jjco/hyaa025.

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Abstract Objective Multidrug resistance and consequent relapse are two major obstacles for treating children with acute lymphoblastic leukemia, the most frequent childhood malignancy. MicroRNAs have potential regulatory roles in response to chemotherapy. The goal of this study was to determine the microRNA that may have effects on the expression level of brain and acute lymphoblastic leukemia (BAALC) and to investigate the in vitro and ex vivo association between their expression levels. Methods In silico tools were utilized to determine a putative miRNA targeting BALLC. Quantitative real-time polymerase chain reaction was used to investigate expression levels of BAALC and its predicted microRNA, miR-326, in bone marrow samples of 30 children with acute lymphoblastic leukemia and 13 controls, in addition to the resistant and parental CCRF-CEM cell lines. To assess the status of response to therapy, minimal residual disease was measured using single-strand conformation polymorphism. Results MiR-326 was selected due to the strong possibility of its interaction with BAALC according to the obtained in silico results. Statistical analysis showed a significant downregulation of miR-326 and overexpression of BALLC in drug-resistant acute lymphoblastic leukemia cell line and patients compared with the parental cell line and drug-sensitive patients, respectively (P = 0.015, 0.005, 0.0484 and 0.0005, respectively). The expression profiles of miR-326 and BAALC were inversely correlated (P = 0.028). Conclusions The results introduced the inversely combined expression levels of miR-326 and BAALC as a novel, independent prognostic biomarker for pediatric acute lymphoblastic leukemia (P = 0.007). Moreover, bioinformatics data showed a possible regulatory role for miR-326 on BAALC mRNA, which may possibly contribute to the development of drug resistance in patients with childhood acute lymphoblastic leukemia.

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Akbari Moqadam, Farhad, Ellen Lange-Turenhout, Arian van der Veer, João R. M. Marchante, Rob Pieters et Monique L. Den Boer. « Expression Pattern Of Mirnas Is Not Predictive For Poor Prognosis In BCR-ABL1-Like Childhood Acute Lymphoblastic Leukemia ». Blood 122, n^o 21 (15 novembre 2013) : 2631. http://dx.doi.org/10.1182/blood.v122.21.2631.2631.

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Abstract Childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is a heterogeneous disease in which the 5-years event-free survival rates are currently above 80%. We recently identified a poor prognostic set of patients within unclassified BCP-ALL patients. These patients have a high risk of relapse and a gene expression profile similar to BCR-ABL1-positive ALL cases. This so-called BCR-ABL1-like (or Ph-like) group of patients showed similar high frequencies of deletion in B-cell development genes (den Boer et al, Lancet Oncology, 2009 and Mullighan et al. New Eng J Med, 2009). Here, we investigate the miRNA expression pattern in BCR-ABL1-like ALL. Further, we addressed whether altered expression levels of discriminative miRNAs of BCR-ABL1-like ALL has prognostic importance. MiRNA expression levels of leukemic cells of 91 newly identified children with BCP-ALL: i.e. 15 BCR-ABL1-like, 14 BCR-ABL1-positive, 9 TCF3-rearranged, 14 hyperdiploid (>50 chromosomes), and 15 B-other patients (negative for BCR-ABL1-like ALL and other known genetic lesions) were measured by Taqman® Array Human miRNA cards (TLDA cards, Applied Biosystems). Using the R statistics program (R-2.15, release June 2012), the Limma package was applied to compare the expression levels of miRNAs between the groups. Each genetic subtype was compared to the remaining cases to identify subtype-specific miRNAs. Our data revealed that children with ETV6-RUNX1-positive, hyperdiploid, TCF3-rearranged and MLL-rearranged ALL demonstrate a subtype-specific miRNA signature. In contrast, BCR-ABL1-positive and BCR-ABL1-like cases showed a more variable miRNA expression pattern, resulting in 2 clusters of patients. The majority of the children with BCR-ABL1-like ALL (11 out of 15) showed a miRNA expression pattern different from that of BCR-ABL1-negative genetic subtypes of pediatric BCP-ALL and cluster with 43% of BCR-ABL1-positive patients (6 out of 14, cluster-I). The remaining 8 BCR-ABL1-positive and 4 BCR-ABL1-like cases showed more heterogeneous expression patterns (cluster-II). The prognosis of patients in both clusters, however, did not differ. Similarly, there was no significant difference in IKZF1, PAX5, JAK2 or CDKN2A/B status between these two clusters. Top-10 most differentially expressed miRNAs of the children with BCR-ABL1-like ALL were miR-324-5p, miR-345, miR-190, miR-130a, miR-545, miR-152, miR-103, miR-191, miR-197 and miR-101. None of these discriminative miRNAs was predictive for clinical outcome of BCR-ABL1-like patients. In conclusion, our data suggest that a miRNA signature is not suitable to dissect good and poor prognostic BCR-ABL1-like cases. Disclosures: No relevant conflicts of interest to declare.

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Narita, Atsushi, Hideki Muramatsu, Nao Yoshida, Hirotoshi Sakaguchi, Sayoko Doisaki, Asahito Hama, Koji Nakanishi et al. « Genetic Events in Ikaros Gene Family (IKZF1 and IKZF2) in Pediatric T-Cell Lymphoblastic Leukemia/Lymphoma ». Blood 120, n^o 21 (16 novembre 2012) : 4622. http://dx.doi.org/10.1182/blood.v120.21.4622.4622.

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Abstract Abstract 4622 The Ikaros gene family, which includes Ikaros (IKZF1), Helios (IKZF2), and Aiolos (IKZF3), is a primary regulator of lymphocyte differentiation and is involved in the development of acute lymphoblastic leukemia (ALL). In particular, loss of IKZF1 is primarily associated with T-cell ALL (T-ALL) development in mouse models. Moreover, Helios expression has been detected in early T-cell lineage and is involved in human lymphoid proliferative disease. We sought to determine whether the Ikaros gene family is associated with leukemogenesis in T-ALL and T-cell non-Hodgkin lymphoma (T-NHL) in Japanese children. Fifty-eight Japanese children (39 boys and 19 girls; age, <18 years) with T-ALL (n = 50) and T-NHL (n = 8) were evaluated. The median age at diagnosis was 8 years (1–15 years). Samples were collected at Japanese Nagoya First Red Cross Hospital and Nagoya University Hospital. Blasts from bone marrow (n = 40), peripheral blood (n = 9), pleural effusions (n = 6), and lymph nodes (n=3) were subjected to DNA extraction. All coding exons in IKZF1 were amplified by polymerase chain reaction using the genomic DNA of patients with T-ALL/T-NHL. After amplification using a BigDye Terminator Cycle Sequencing kit (Life Technologies, Carlsbad, CA, USA) in the second step, products were analyzed in an ABI/PRISM 3130xl Genetic Analyzer (Life Technologies). Multiplex ligation-dependent probe amplification (MLPA) analyses were performed using a SALSA MLPA reaction mixture according to the manufacturer's protocol [P202 kit; IKZF1(IKAROS); MRC-Holland, Amsterdam, Netherlands]. Amplification products were quantified and identified by capillary electrophoresis on an ABI/PRISM 3130xl Genetic Analyzer. Informed consent was received from parents of the patients. Approval for this study, including molecular analyses, was obtained from the institutional ethics committee of Nagoya University Graduate School of Medicine. An IKZF1 mutation was found in only 1 of 59 (2%) patients (exon 5, c.476 A>G, p.N159S; patient number 41) who was diagnosed with primary immune deficiency after birth. She received regular immunoglobulin replacement therapy just before the development of T-ALL at 13 years of age. Her IKZF1 mutation was confirmed as a germline mutation by sequencing of genomic DNA from her fingernails. In the IKZF1 null mouse model, Ikaros inactivation is closely linked to T-ALL development, which is highly associated with acquisition of a somatic NOTCH1 mutation. As in the mouse model, we could identify a somatic NOTCH1 mutation (exon 26, c.4750, insGAG) in the sample upon T-ALL development. IKZF1 mutations were not found in the other 57 samples. This finding implied that the IKZF1 mutation was a rare genetic event in de novo T-ALL/T-NHL in children. Furthermore, we analyzed all samples by MLPA to determine if monoallelic genomic deletions were present. Although 59 samples exhibited normal biallelic IKZF1 and IKZF3 chromosomal regions, we identified IKZF2 microdeletions in 2 (3.4%) patients (numbers 9 and 49). One of them with an IKZF2 microdeletion died of leukemia relapse after allogeneic bone marrow transplantation from a human leukocyte antigen (HLA)-matched sibling donor. Overexpression of full-length Helios (IKZF2) blocks αβ T-cell differentiation at the CD4-CD8- stage in the thymus, and results in the increased frequencies of γδ T and natural killer (NK) cells in peripheral lymphoid organs. Overexpression of dominant negative Helios leads to increased T-cell proliferation upon T-cell receptor stimulation and the development of T lymphoma. Furthermore, dominant negative Helios isoforms or allelic losses have been detected in some human T-ALL/T-NHL. These results suggest that Helios is an essential regulator of T-cell homeostasis and a tumor suppressor. In general, IKZF1 mutation or deletion is a rare event in pediatric patients with T-ALL/T-NHL. We could identify a secondary T-ALL patient after primary immunodeficiency who shared genetic findings with an IKZF1 null mouse model (germline IKZF1 mutation and somatic NOTCH1 mutation). We found IKZF2 microdeletion in 2 of 59 patients. The genetic events in the Ikaros gene family (IKZF1 and IKZF2) are associated with leukemogenesis in a few pediatric patients T-ALL/T-NHL. Disclosures: No relevant conflicts of interest to declare.

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Abd El Hassib, Dalia M., Nevein A. Abdulhafeez, Ola M. Atef et Seham G. Ameen. « The role of miRNA-196a2 genotypes in the susceptibility of acute lymphoblastic leukemia in Egyptian children ». Gene Reports 24 (septembre 2021) : 101237. http://dx.doi.org/10.1016/j.genrep.2021.101237.

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Kuiper, Roland P., Frank N. van Leeuwen, Vincent van der Velden, Simon V. van Reijmersdal, Jeltje de Vries, Suzanne T. M. Keijzers-Vloet, Jayne Hehir-Kwa et al. « Ikaros Is a Frequently Affected Hematopoietic Differentiation Factor in Pediatric Relapse-Prone Precursor B-Cell Acute Lymphoblastic Leukemia ». Blood 112, n^o 11 (16 novembre 2008) : 4144. http://dx.doi.org/10.1182/blood.v112.11.4144.4144.

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Abstract Relapse is the most common cause of treatment failure in childhood acute lymphoblastic leukemia (ALL), and is difficult to predict in the majority of cases. Here, we performed genome-wide copy number profiling of 34 paired diagnosis-relapse samples from children diagnosed with precursor-B cell ALL. The majority of the copy number abnormalities were preserved between matched diagnosis and relapse samples, but lesions unique in either of the two samples were observed in 82% of the cases. In 68% of the cases lesions present at diagnosis were no longer detected in relapse samples (including recurrent lesions affecting the PAX5, CDKN2A, and EBF genes), indicating that these lesions were secondary events, absent in the original therapy-resistant progenitor clone. Deletions in the IKZF1 gene encoding the hematopoietic differentiation factor Ikaros were observed in 38% of the diagnosis samples, which is >6-fold the amount detected in an unselected group of pediatric ALLs. Tiling-resolution oligo arrays were used to map the breakpoints, which demonstrated that the protein-coding exons 3–6, encoding the DNA-binding Zn-finger domains, were most commonly deleted. Sequence analysis revealed that point mutations in IKZF1 do occur but are less frequent. Furthermore, IKZF1 deletions were always preserved in relapse. Together, we conclude that IKZF1 deletions are frequent events in therapy-resistant clones of relapse-prone pediatric precursor B-ALL.

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Drobna, Monika, Bronislawa Szarzynska-Zawadzka, Maria Kosmalska, Roman Jaksik, Tomasz Szczepanski, Michał Witt et Małgorzata Dawidowska. « miR106a-363 Cluster Has Oncogenic Potential in Childhood T-Cell Acute Lymphoblastic Leukemia ». Blood 132, Supplement 1 (29 novembre 2018) : 5142. http://dx.doi.org/10.1182/blood-2018-99-111103.

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Abstract T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy originating from T-cell precursors and is characterized by high genetic, immunophenotypic, and clinical heterogeneity. MicroRNAs (miRNAs) belong to the class of small noncoding RNAs and are implicated in the regulation of hematopoiesis and in the development of leukemia. miRNAs control expression of their target genes at the post-transcriptional level by blocking translation of messenger RNAs (mRNAs) or promoting their degradation. Some miRNAs are encoded within clusters, giving rise to policistronic transcripts. Such miRNAs are co-expressed and may co-regulate the expression of genes involved in certain biological processes and pathways. In our recent study we performed miRNA profiling in pediatric T-ALL using Next-Generation Sequencing (Dawidowska M et al. Blood 2017; 130:1443) and identified miRNAs differentially expressed in T-ALL. The set of overexpressed miRNAs included, among others, miR-20b-5p, miR-363-3p and miR-92a-2-5p, belonging to a cluster of six miRNAs: miR-106a-363 (ChrXq26.2). miR-106a-363 cluster is a paralog of miR-17-92 cluster (Chr13q31.3), a prototypic oncogenic cluster of eminent importance in human hematopoietic cancers, with reported role in T-ALL pathogenesis (Mavrakis KJ et al., Nature Cell Biology 2010, 12:4). Despite the similarity of seed sequences between miRNAs from miR-17-92 and miR-106a-363 clusters, the significance of miR-106a-363 cluster in T-ALL remains to be elucidated. In this study we investigated the expression of the miR-20b-5p, miR-363-3p and miR-92a-2-5p in children with T-ALL, healthy donor thymocytes, normal bone marrow samples and 6 T-ALL cell lines. RT-qPCR analysis (TaqMan Advanced miRNA Assays; Thermo Fisher Scientific) confirmed overexpression of 2 miRNAs from cluster miR-106a-363 (miR-20b-5p and miR-363-3p) in children with T-ALL and in T-ALL cell lines, suggesting their oncogenic function. To predict potential target genes of overexpressed miRNAs belonging to miR106a-363 cluster, we applied 8 target prediction algorithms and pathway enrichment analysis. This revealed the enrichment of miR-20b-5p and miR-363-3p target genes in GO term: positive regulation of apoptosis. We further validated predicted miRNA-mRNA interactions (Dual Luciferase Reporter Assays; Promega) confirming the majority of them (e.g. PTEN, FBXW7, BCL2L11). Finally, we assessed the effect of mimicry/inhibition (miRVana, Thermo Fisher Scientific) of overexpressed miRNAs from miR-106a-363 cluster on proliferation, cell cycle distribution and apoptosis in 3 T-ALL cell lines. Overexpression of miR-20b-5p and miR-363-3p in CCRF-CEM, DND-41 and P12-Ichikawa cells resulted in increased proliferation and inhibited apoptosis. To summarize, in this study we showed that miRNAs belonging to miR-106a-363 cluster directly interact with mRNAs implicated in the regulation of apoptosis and that miR-20b-5p and miR-363-3p have pro-proliferative and anti-apoptotic effects in T-ALL cells in vitro. These results indicate that miR-106a-363 cluster may have an oncogenic role in the pathogenesis of T-ALL via suppression of pro-apoptotic genes. Research funded by National Science Centre, Poland grants: 2014/15/B/NZ2/03394, 2017/25/N/NZ2/01132 and National Centre of Research and Development (NCRD) grant STARTEGMED3/304586/5/NCBR/2017. Disclosures No relevant conflicts of interest to declare.

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Mosakhani, Neda, Mohamed El Missiry, Emmi Vakkila, Päivi Heikkilä, Sakari Knuutila et Jukka Vakkila. « Low Epression of MiR-18a Distinguishes Pediatric and Adult Acute Lymphoblastic Leukemia from Each Other ». Blood 126, n^o 23 (3 décembre 2015) : 4991. http://dx.doi.org/10.1182/blood.v126.23.4991.4991.

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Abstract In several adult solid cancers the presence or absence of an inflammatory microenvironment has turned out to be an important prognostic factor. Acute lymphoblastic leukemia (ALL) is seen in both adults and children but the response to chemotherapy and survival is significantly worse in adults than children. Therefore, we wanted to study whether the expression of immune system associated molecular markers would be different in adult and pediatric ALL patients at the time of diagnosis. IDO and FOXP3 were studied from paraffin embedded tissue samples by immunohistochemistry in 12 pediatric and 10 adult bone marrow samples. Inflammation associated miRNA analysis were performed in 19 adult and 79 pediatric ALL patients and involved miR-10, miR-15, miR-16, miR-17-92 cluster, miR-33, miR-146a, miR-150, miR-155, miR-181a, miR-222, miR-223, and miR-339. miRNAs were first analysed by Agilent's miRNA microarray and thereafter validated by qRT-PCR. miRNAs not expressed in at least 75% of one group of samples were excluded. Significance (p <0.05; q<0.1) of differential expression was estimated by t-test for those miRNAs with at least a 2.0 fold change. Sufficient RNA for qRT-PCR was available for 42 pediatric and 19 adult patients. The adult and pediatric ALL patients had quantitatively and qualitatively similar expression of IDO and FOXP3 in leukemic bone marrow samples (p=0.26 and 0.74, respectively). Out of studied miRNAs only miR-18a differed significantly in microarray analysis between adult and pediatric ALL being lower in children (FC -3.74; p 0,0037). Results were confirmed by qRT-PCR (upregulated in adults, FC 3.71, p 0.003161). The other members of the miR-17-92 cluster did not differ significantly. We conclude that pediatric and adult ALL patients have remarkably similar pattern of immune cell associated markers in bone marrow at diagnosis. This is in line with recent evidence that the outcome of the adult ALL patients can be significantly improved if treated with pediatric protocols. However, the low expression of miR-18a in pediatric ALL is interesting and demands further studies. Disclosures No relevant conflicts of interest to declare.

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Avigad, Smadar, Iedan RN Verly, Gertjan J. L. Kaspers, Jacqueline Cloos, Anat Ohali, Michal Hameiri-Grossman, Eva Fonkova et al. « Low Levels of Mir-151-5p and Mir-451 Predict Relapse in Pediatric B-Lineage Acute Lymphoblastic Leukemia. » Blood 120, n^o 21 (16 novembre 2012) : 2507. http://dx.doi.org/10.1182/blood.v120.21.2507.2507.

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Abstract Abstract 2507 Aim: microRNAs (miRNAs) have been implicated in many malignancies. Our aim was to identify specific miRNAs that can predict risk of relapse in pediatric acute lymphoblastic leukemia (ALL) patients treated according to BFM protocols already at diagnosis. The current risk group stratification is based on the amount of minimal residual disease (MRD) assessed at specific time points by real time quantitative PCR (RQ-PCR). Material and methods: Following miRNA expression analysis, we decided to focus on miR-151-5p and miR-451 that significantly correlated with known prognostic factors in ALL. Validation was performed by measuring the expression levels of miR-151-5p and miR-451 by RQ-PCR on bone marrow samples at diagnosis of 101 B-lineage ALL patients excluding Philadelphia positive patients. Results: Low expression of miR-151-5p, miR-451 or of both together resulted in significantly worse relapse free survival (RFS) (43%, 58% and 38%, respectively) compared to RFS rates when either or both miRNAs were highly expressed (81%, 75% and 75%, respectively) (p=0.001, 0.044 and 0.001, respectively). Moreover, following PCR-MRD stratification, low expression of miR-451 or both miRNAs remained significant within the PCR-MRD medium risk group (p=0.00001) and within the standard group for both miRNAs (p=0.024). Multivariate Cox regression analysis identified low expression of both miRNAs as an independent prognostic marker with 11.7 fold increased risk for relapse (p=0.002). After excluding patients harboring the adverse genetic markers Ikaros deletion and P2RY8-CRLF2 rearrangement, a patient expressing low levels of both miRs had a 35 fold risk to relapse (p=0.005). Analyzing a non-BFM treated B-lineage ALL cohort from The Netherlands, both miRNAs significantly correlated with outcome (p=0.003). Conclusion: Our results identify miR-151-5p and miR-451 as novel biomarkers for outcome in pediatric B-lineage ALL patients, regardless of treatment protocol. This may allow earlier and improved risk group stratification already at diagnosis, enabling exploration of early therapeutic interventions. Disclosures: No relevant conflicts of interest to declare.

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Ross, Julie A., Amy M. Linabery, Crystal Blommer, Erica Langer, Logan G. Spector, Joanne M. Hilden, Nyla A. Heerema, Richard L. Tower et Stella M. Davies. « Genetic Susceptibility Loci and Risk of Infant Leukemia by Subtype and MLL status : A Children's Oncology Group Report ». Blood 118, n^o 21 (18 novembre 2011) : 749. http://dx.doi.org/10.1182/blood.v118.21.749.749.

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Abstract Abstract 749 Introduction. Leukemia in infancy is extremely rare and etiologically distinct from leukemia arising in older children. Infant leukemia cases likely arise in utero, typically involve rearrangements of the mixed lineage leukemia (MLL) gene, and have a much poorer survival than older children with leukemia. Since genetic determinants of susceptibility to infant leukemia are likely different from those in older children, we aimed to evaluate genetic variants previously identified by genome wide association studies of childhood acute lymphoblastic leukemia (ALL). Methods. We genotyped candidate susceptibility loci in 171 Caucasian infants less than 12 months of age with acute leukemia (including 102 ALL, 67 acute myeloid leukemia (AML), and 2 biphenotypic cases) diagnosed during the period 1996–2006. Controls consisted of 384 healthy Caucasian blood donors. Associations between genetic polymorphisms in IKZF1, ARID5B, and CEBPE and infant leukemia were evaluated using logistic regression and were further stratified by leukemia subtype and presence or absence of MLL gene rearrangements. Results. We observed a statistically significant association with two copies of the IKZF1 rs11978267 variant allele in infant leukemia overall (Odds Ratio (OR)=2.3, 95% Confidence Interval (CI)=1.3-4.2), but not with the other susceptibility loci. The association with IKZF1 was concentrated in the AML group, with an increased risk associated with two copies of the variant allele (OR=3.9, 95%CI=1.8-8.4), but not one copy. The association was similarly strong in those with and without a MLL gene rearrangement. In contrast, a strong association with the IKZF1 variant was seen in infants with ALL lacking a MLL rearrangement (OR=5.1, 95%CI=1.8-14.5), but not in those with MLL rearrangements (OR=0.7, 95%CI=0.2-2.2). Moreover, infants with ALL and no MLL rearrangement had a strong association with a genetic variant in the gene, ARID5B (rs10821936, OR=7.2, 95%CI=2.5-20.6), which was also not seen in those with ALL and a MLL rearrangement. Discussion. IKZF1 (IKAROS)is expressed in early hematopoiesis, and its role in lymphopoiesis and lymphoid leukemia is well-described. IKAROS is also expressed in precursor myeloid cells, and our report is the first evidence that IKZF1 is important in the etiology of infant myeloid leukemia, irrespective of MLL gene rearrangements. Moreover, our data indicate striking differences in genetic susceptibility to infant ALL with and without rearrangements of the MLL gene. This knowledge could provide important new etiologic insights into this extremely rare but heterogeneous hematopoietic malignancy. Supported by NIH CA079940, T32 CA099936, K05 CA157439 and the Children's Cancer Research Fund, Minneapolis, MN. Disclosures: No relevant conflicts of interest to declare.

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Oosterom, Natanja, Ángela Guttiérez-Camino, Marissa Den Hoed, Elixabet López-López, Saskia MF Pluijm, Rob Pieters, Robert de Jonge et al. « CNOT1 Microrna Single Nucleotide Polymorphism (SNP) Determines the Occurrence of Methotrexate Related Mucositis in Pediatric Acute Lymphoblastic Leukemia ». Blood 126, n^o 23 (3 décembre 2015) : 1237. http://dx.doi.org/10.1182/blood.v126.23.1237.1237.

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Abstract BACKGROUND Cure rates of pediatric acute lymphoblastic leukemia (ALL) have reached 90% in the developed countries. However, toxicity due to chemotherapeutic regimens occurs frequently but with great heterogeneity. This suggests that genetic variation is involved. In order to identify determinants of adverse effects, recent studies have investigated pharmacogenetic features in relation to toxicity. Most of these studies examined coding regions of the genome. Recently, it has been described that epi genetic regulators, such as micro-RNA's (miRNA), might also have an important regulatory function in genes involved in drug related toxicity. In a recent study 25 miRNA SNPs were found to be related to toxicity in pediatric ALL treatment (Lopez-Lopez, PLoS ONE, 2014). In pediatric ALL mucositis is one of the most frequent side effects during high dose methotrexate (MTX) treatment. AIM The aim of this study was to detect novel, epigenetic biomarkers that predict MTX related oral mucositis in pediatric acute lymphoblastic leukemia (B- and T cell) by studying single nucleotide polymorphisms (SNP) involved in miRNA levels and function. METHODS DNA was isolated from whole blood of 118 pediatric ALL patients that were treated with high dose MTX (5 gr/m2) according to the Dutch Childhood Oncology Group ALL-10 protocol. The recently published 25 SNPs, involved in miRNA function and located in the DROSHA, CNOT1, CNOT4, EIF2C1, GEMIN3, GEMIN4, MIR604, MIR453, MIR2110, MIR2053, MIR1294, MIR1206, DICER, XPO5 and TNRC6B genes, were selected for genotyping. Toxicity data during the consolidation phase were prospectively collected and documented according to the National Cancer Institute (NCI) v.3.0 score system. Mucositis NCI grade ≥ 3 (grade 3: confluent ulcerations, bleeding with minor trauma), was considered as clinical significant toxicity and was used as endpoint. RESULTS Mucositis was the only recurring toxicity in this prospectively well-documented cohort and therefore used as endpoint of this study. A selection of 20 of the previously identified 25 candidate SNPs was studied based on technical feasibility. In addition, 1 SNP in the XPO 5 gene was not considered for analysis because it was not in Hardy Weinberg equilibrium. Mucositis occurred in 19% of the patients in at least one of the MTX courses. Only the TT genotype of rs11866002 in the CNOT1 (CCR4-NOT complex, subunit 1) gene was associated with a higher risk of developing mucositis (NCI ≥ 3) compared to carries of CC/CT. The other 18 candidate SNPs analyzed did not show statistically significant associations. CONCLUSION The inter-patient variability of mucosal toxicity was not associated with most of our investigated SNPs which are involved in miRNA transcription and function. CNOT1 rs11866002 C>T was the only single nucleotide polymorphism associated with the occurrence of oral mucositis during pediatric acute lymphoblastic leukemia treatment. We acknowledge the Foundation Children Cancerfree (KiKa), Amstelveen, The Netherlands, for funding this research. Disclosures No relevant conflicts of interest to declare.

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Kang, Huining, I. Ming Chen, Carla S. Wilson, Edward J. Bedrick, Richard C. Harvey, Susan R. Atlas, Meenakshi Devidas et al. « Gene expression classifiers for relapse-free survival and minimal residual disease improve risk classification and outcome prediction in pediatric B-precursor acute lymphoblastic leukemia ». Blood 115, n^o 7 (18 février 2010) : 1394–405. http://dx.doi.org/10.1182/blood-2009-05-218560.

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Abstract To determine whether gene expression profiling could improve outcome prediction in children with acute lymphoblastic leukemia (ALL) at high risk for relapse, we profiled pretreatment leukemic cells in 207 uniformly treated children with high-risk B-precursor ALL. A 38-gene expression classifier predictive of relapse-free survival (RFS) could distinguish 2 groups with differing relapse risks: low (4-year RFS, 81%, n = 109) versus high (4-year RFS, 50%, n = 98; P < .001). In multivariate analysis, the gene expression classifier (P = .001) and flow cytometric measures of minimal residual disease (MRD; P = .001) each provided independent prognostic information. Together, they could be used to classify children with high-risk ALL into low- (87% RFS), intermediate- (62% RFS), or high- (29% RFS) risk groups (P < .001). A 21-gene expression classifier predictive of end-induction MRD effectively substituted for flow MRD, yielding a combined classifier that could distinguish these 3 risk groups at diagnosis (P < .001). These classifiers were further validated on an independent high-risk ALL cohort (P = .006) and retainedindependent prognostic significance (P < .001) in the presence of other recently described poor prognostic factors (IKAROS/IKZF1 deletions, JAK mutations, and kinase expression signatures). Thus, gene expression classifiers improve ALL risk classification and allow prospective identification of children who respond or fail current treatment regimens. These trials were registered at http://clinicaltrials.gov under NCT00005603.

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Iacobucci, Ilaria, Monica Messina, Nunzio Iraci, Annalisa Lonetti, Sabina Chiaretti, Anna Ferrari, Cristina Papayannidis et al. « IKZF1 (IKAROS) Deletions Are Independent On BCR-ABL1 Rearrangement and Are Associated with a Peculiar Gene Expression Signature and Poor Prognosis in Adult B-Progenitor Acute Lymphoblastic Leukemia (ALL) Patients. » Blood 114, n^o 22 (20 novembre 2009) : 912. http://dx.doi.org/10.1182/blood.v114.22.912.912.

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Abstract Abstract 912 Background: Recent genome-wide analyses in B-precursor acute lymphoblastic leukemia (ALL) demonstrated that deletions of IKZF1, which encodes the transcription factor Ikaros, play an important role in the pathogenesis of BCR-ABL1-positive and BCR-ABL1-like acute leukemias. IKZF1 deletions have been associated with poor outcome in children with ALL but a full understanding of their biological implications and clinical significance has not yet been defined in adult patients. Purpose and Methods: In order to address this issue and to evaluate whether the cases harbouring IKZF1 alterations display a peculiar gene expression profile, a cohort of 144 adult de novo ALL patients (106 BCR-ABL1-postive and 38 B-progenitor ALL negative for known molecular rearrangements) were analyzed with the use of single-nucleotide–polymorphism (SNP) microarrays (Affymetrix 250K NspI and SNP 6.0), FISH for IKZF1 deletions and gene expression profiling (HGU133 Plus 2.0 gene chips, Affymetrix). Patients had a median age of 49 years (range 18-78) and were enrolled into institutional (n = 17) or GIMEMA AL Working Party (n = 121) clinical trials. Results: Deletions of IKZF1 were identified in 75% adult BCR-ABL1-positive and in 58% BCR-ABL1-negative ALL cases, suggesting that IKZF1 deletion is more frequent in the BCR-ABL1-positive ALL subtype (p= 0.04). FISH analysis using a pool of fosmid probes for IKZF1 and genomic quantitative PCR confirmed SNP results. Among 144 patients, the entire IKZF1 locus was deleted in 18 (13%) whereas in 84 (58%) patients only a subgroup of exons or the genomic region immediately upstream of IKZF1 was deleted. In particular, in 46 patients (32%) there was a deletion of the coding exons 4 through 7, which resulted in the expression of a dominant-negative isoform, Ik6, lacking the DNA binding domain. In 24 cases (17%) we identified the loss of exons 2 through 7, producing an Ikaros isoform lacking the translation start site. Using gene-set enrichment analysis to compare the gene-expression data from patients with IKZF1 deletion versus wild-type patients, we identified a peculiar signature irrespective of BCR-ABL1 rearrangement but dependent on IKZF1 genomic status. Indeed, it was characterized by the presence of two subgroups of genes, the expression of which was deregulated in a reciprocal fashion. One subgroup was enriched with up-regulated genes involved in cell-cycle progression (STK17B, SERPINB9, CDKN1A), activation of signalling via JAK-STAT pathway (CISH, SOCS1, SOCS3, STAT3) and DNA damage (GADD45A, GADD45B, NFKBIA, the protoncogene REL). The second subgroup contained down-regulated genes, which are normally expressed during lymphocyte differentiation (e.g. VPREB1, VPREB3, IGLL3, BLK) or are involved in DNA damage repair (MSH2, MSH6) supporting the hypothesis that B-ALL cells with IKZF1 deletions are prone to a block of B-cell differentiation and accumulation of DNA damage events. To investigate whether Ikaros transcription factor is directly involved in the regulation of putative target genes identified in gene expression analysis, cross-linking chromatin immunoprecipitation (ChIP) assay was performed in cell lines and primary ALL cells. We found that the promoters of IGGL1, CD79A, BLK, EBF1, BLC2, MSH2, BUB3, ETV6, YES1, CDKN1A (p21) and CDKN2C (p18) genes, were bound in vivo only by Ikaros full-length protein, but not by Ik6 mutant. These data strongly support a model in which Ikaros deleted isoforms loose the ability to regulate a large set of genes, many of which may play crucial roles in B-ALL development. We next investigated whether the IKZF1 deletions associated with a poor outcome in ALL patients. Univariate analysis showed that the IKZF1 deletion negatively influenced the cumulative incidence of relapse (p=0.02) and disease-free survival (p=0.04, Wilcoxon test) as confirmed by multivariate analysis. Conclusion: In conclusion, our findings shed light on a new subgroup of adult ALL including BCR-ABL1 positive and BCR-ABL1 negative patients and characterized by a unique signature dependent on Ikaros genomic status. Loss of normal Ikaros activity results in the activation of JAK-STAT pathway, DNA repair gene down-regulation and a block of B-cell differentiation. Supported by: European LeukemiaNet, AIL, AIRC, FIRB 2006, Strategico di Ateneo, GIMEMA Onlus. Disclosures: No relevant conflicts of interest to declare.

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Perdana, Adhitya Bayu, Fahreza Saputra et Mururul Aisyi. « Update on Diagnosis of Childhood Acute Lymphoblastic Leukemia (ALL) in Indonesia ». Indonesian Journal of Cancer 14, n^o 4 (28 décembre 2020) : 115. http://dx.doi.org/10.33371/ijoc.v14i4.818.

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Childhood cancer has been a global public health scourge with considerably escalating incidence each year [1]. Although the incidence is relatively lower compared to adult malignancies, it remains the leading cause of disease-related death in children. The most frequent childhood cancer is acute lymphoblastic leukemia (ALL) with an annual incidence of 3.5 per 100,000 children in the United States [2]. Similarly, in Indonesia, ALL has the highest number of cancer cases in children [3]. The total incidence of ALL in Indonesia reaches 2.5-4.0 per 100,000 children with an estimated 2,000-3,200 annually [4]. Because of its high incidence and curability, ALL is a logical initial objective for childhood cancer program developments in Indonesia. As an indicator of successful treatment of childhood ALL, the 5-year survival rate shows contrasting figures between high-income (HIC) and lower-middle-income countries (LMIC). In the United States and most European countries, the survival rates are approximately 90% and 85% respectively. However, in Southeast Asian countries, the highest 5-year survival rate for children aged 0 to 14 was reported in Malaysia (69.4%), followed by Thailand (55.1%) [5]. Furthermore, more unfavorable results were reported in Indonesia. Studies from Dharmais Cancer Hospital and Dr. Sardjito Hospital reported the 5-year survival rate of 28.9% and 31.8% respectively [6,7]. The outcome difference between Indonesia and other countries is probably due to the high rate of relapse occurrence and toxic death during the treatment. Some studies revealed the factors that affecting the worst outcome of childhood ALL in LMIC include inadequate and delayed diagnosis, limited healthcare access, treatment abandonment, and suboptimal supportive care [8]. As pediatric oncologists in HIC have become more effective at treating childhood ALL, much of the research attempts concentrated on the risk stratification of the patients. The term “risk stratification” is used to allocate the patients into various risk groups based on the notable prognostic features for specific treatment administration. Patients with a high-risk assessment could be targeted for more aggressive treatments, while patients with lower risk could be treated less intensively to avoid the side effects and toxicities [9]. In Indonesia, risk stratification strategy encompasses clinical-hematologic parameters (age, leukocyte count, extramedullary involvement), and conventional morphological examination. These assessments represent the first step in the diagnostic pathway of ALL. Though helpful, in certain cases, the residual leukemic cells might be undetectable under bone marrow morphology examination. This led to more underdiagnosed cases, thus more patients were subjected to inadequate treatment. Fortunately, immunophenotyping is currently applied to improve the diagnosis of childhood ALL by grouping the patients based on the aberrant expression of leukemic cell antigen, even though its application is only available in several centers including Dharmais Cancer Hospital. The BCR-ABL1 fusion gene examination by PCR-based techniques has also routinely been implemented to predict the poor outcome since it was detected in 12% of childhood ALL patients [10]. However, the current above-mentioned strategy is insufficient to solve the accuracy of risk stratification of childhood ALL. In HIC, childhood ALL are classified by more comprehensive examination involving morphology, immunophenotyping, cytogenetics, and molecular techniques. The approach to classifying prognosis and to personalize treatment based on the underlying genetic biology has already implemented for understanding the pathogenesis of childhood ALL. According to studies, the molecular features of childhood ALL have been shown to have a significant prognostic value [11], and the survival rate was improved when genetic examinations are applied [12]. In recent years, high-resolution array-based genomic technologies have revolutionized the understanding of the genetic basis of childhood ALL. Several biomarkers have successfully been identified that are provenly associated with poor prognosis in childhood ALL, including the deletion/mutation of IKZF1 (IKAROS), CDKN2A, ETV6, EBF1, JAK2, and many more [13]. The majority of these genetic changes were originally identified by sophisticated methods such as single nucleotide polymorphism (SNP) arrays, gene expression profiling (GEP), array-based comparative genomic hybridization (aCGH), and more recently next-generation sequencing (NGS) [14]. Despite being highly sensitive for detection of multiple copy number changes, these approaches are not feasible for routine diagnostic use in LMIC which requires significant EDITORIAL Indonesian Journal of Cancer, Vol 14(4), 115–116, December 2020 DOI: http://dx.doi.org/10.33371/ijoc.v14i4.818 www.indonesianjournalofcancer.or.id P-ISSN: 1978-3744 E-ISSN: 2355-6811 116 | financial investment. Therefore, molecular techniques that suit available resources and infrastructure should be developed in LMIC, and most importantly the cost should be affordable for patients. One feasible method is Multiplex Ligation-dependent Probe Amplification (MLPA). MLPA is a rapid multiplex PCR-based technique that enables the comparative analysis of multiple mutation spots [15]. MLPA provides a low-cost, simple alternative to array-based techniques for much routine clinical practice, even though it is unsuitable for whole-genome analysis. Furthermore, one benefit compared to other quantitative PCR-based techniques is that MLPA allows 50 or more different genomic DNA to be analyzed in a single tube reaction. Several studies have demonstrated the implementation of specific MLPA probe mixes for hematological malignancies, including ALL, chronic lymphocytic leukemia (CLL), and myelodysplastic syndrome (MDS). These studies have also shown the sensitive and accurate identification of clinically significant diseasespecific copy number changes [16]. Currently, MLPA has been established as a routine diagnostic of childhood ALL patients in Dharmais Cancer Hospital by a research-based service setting. It reliably detects small focal deletions, even from the low amount of specimens. In general, the results demonstrated the concordance between mutated genes reported in highrisk patients (deletion of IKZF1, CDKN2A, CDKN2B, PAX5). These findings surely can guide the doctors in Dharmais Cancer Hospital to assign the specific patients for the intensive treatment protocol, which is expected to increase the patient’s survival. Therefore, concerning the future clinical application, the inclusion of mutation status by MLPA for childhood ALL risk stratification should be widely promoted to a large health community, especially the Indonesian Pediatric Society, which views this as a consideration for refinement of standard diagnosis protocol for childhood ALL in Indonesia.

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Churchman, Michelle L., Maoxiang Qian, Ranran Zhang, Geertruy Kronnie, Wenjian Yang, Hui Zhang, Tobia Lana et al. « Germline Genetic Variation in IKZF1 and Predisposition to Childhood Acute Lymphoblastic Leukemia ». Blood 128, n^o 22 (2 décembre 2016) : LBA—2—LBA—2. http://dx.doi.org/10.1182/blood.v128.22.lba-2.lba-2.

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Abstract Background There is increasing evidence for an inherited predisposition to pediatric acute lymphoblastic leukemia (ALL). We and others have previously reported rare and highly penetrant variants in hematopoietic transcription factors (PAX5 and ETV6) and tumor suppressor genes (TP53) in both sporadic and familial ALL. IKZF1encodes the founding member of the Ikaros family of zinc finger transcription factors, and is a critical regulator of lymphoid development. IKZF1 is frequently targeted by somatic deletions and mutations in high-risk B-ALL, particularly Ph+ and Ph-like ALL, and is associated with poor outcome. IKZF1 alterations have previously been shown to result in the acquisition of stem cell-like features, overexpression of adhesion molecules causing aberrant cell-cell and cell-stroma interaction, and decreased sensitivity to tyrosine kinase inhibitors. Genome-wide association studies have also identified an association between common polymorphisms at the IKZF1locus and risk of developing ALL, however the nature and effects of germline IKZF1variation in the pathogenesis of ALL are poorly understood. In this study, we sought to comprehensively characterize germline IKZF1 genetic variation and to determine the extent to which they contribute to predisposition to ALL. Methods We recently identified a germline frameshift IKZF1 variant (D186fs) in the proband of a family with BCR-ABL1 ALL with incompletely penetrant autosomal dominant inheritance, and carriers of this variant showed varying degree of B cell deficiency. We sequenced IKZF1in germline DNA from 5,008 children with ALL (4902 B-ALL and 106 T-ALL) enrolled on ChildrenÕs Oncology Group and St. Jude ChildrenÕs Res. Hosp. frontline ALL trials. We examined each variant for its effects on transcriptional repression, DNA-binding, cellular localization, homodimerization, and leukemic cell adhesion in mouse BCR-ABL1Arfnull B-ALL cells and/or in HEK 293T cells. All variants were assayed for their effects on cell viability and proliferation, cell-cell adhesion, and IKZF1 protein expression and localization in BCR-ABL1 Arfnull pre-B cells. Representative variants, including M31V (N-term), H163Y (DNA-binding domain), D186Tfs (familial index), M306* (truncation of C-terminus), and A434G (C-terminus) were also assayed in detail for their ability to dimerize with wild type IKZF1, bind to DNA, or dominant negative effects on transcription repressor activity in HEK293T cells. IKZF1 variants were also evaluated for inducing perturbations in cell adhesion and THY1, ITGA5, SELL expression in the mouse PreB cells, and adhesion within the bone marrow niche by ex vivo imaging of calvaria. Finally, the effects of variants on dasatinib sensitivity were assessedin vitro and in vivo. Results We identified 28 germline IKZF1variants in children with ALL, mostly in B-ALL (Figure 1). Among these variants, 3 were frameshift or nonsense resulting in truncated IKZF1 proteins. Of the remaining missense variants, 2 were located within the N-terminal DNA-binding domain, 1 in the C-terminal dimerization domain, and 22 in other parts of IKZF1 protein with clustering proximal to the C-terminal zinc fingers. In mouse BCR-ABL1 Arfnull pre-B cells, all but 4 variants (P18T, P420Q, H432Q, and M518K) variably perturbed IKZF1 function. In contrast to expression of wild-type IKZF1, which caused growth arrest, 24 of the ALL variants were tolerated; 18 caused cellular aggregation; 15 displayed cytoplasmic mislocalization; and 14 out of 20 variants analyzed had significant upregulation of the adhesion molecules THY1, ITGA5 and/or SELL that are normally repressed by IKZF1. In HEK293T cells, 3 IKZF1 truncating variants showed dramatic loss of transcription repressor activity and no longer dimerized with wildtype IKZF1. DNA-binding domain variants (R162P, H163Y) failed to repress target promoter transcription but also altered wildtype IKZF1 function in a dominant negative fashion. In comprehensively characterization of representative variants (M31V, H163Y, D186Tfs, M306X, and A434G), these variations caused cell-stroma adherence in the bone marrow niche in vivo, and significantly reduced sensitivity of leukemic cells to dasatinib in vitro and in vivo. Conclusions These results identify IKZF1 as a new ALL predisposition gene, and suggest that these germline risk variants have roles in both leukemia pathogenesis and treatment responsiveness. Disclosures No relevant conflicts of interest to declare.

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Galbiati, Marta, Antonella Lettieri, Simona Songia, Cristina Morerio, Concetta Micalizzi, Carlo Dufour, Andrea Biondi et Giovanni Cazzaniga. « Acute Lymphoblastic Leukemia Natural History in Neurofibromatosis Type 1 Monozygotic Twins ». Blood 118, n^o 21 (18 novembre 2011) : 2414. http://dx.doi.org/10.1182/blood.v118.21.2414.2414.

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Abstract Abstract 2414 Introduction: Neurofibromatosis 1 (NF1) is an autosomal dominant disease, caused by mutation of neurofibromin (NF1) gene, located in the 17q11.2 chromosomal region. Children affected by NF1 have an increased risk to develop tumors, including leukemia. It has been suggested that NF1 aberrancy is a tumor predisposing factor, and that secondary events in somatic cells gives rise to the formation of neoplasm. However, the clonal evolution from NF1 mutation to tumor development has never been elucidated. Monozygotic twins constitute an ideal tool to understand the clonal evolution of leukemia in the context of a common genetic background. Patients: We performed the genomic characterization of a pair of monozygotic twins with diagnosis of NF1, who developed concordant B-cell precursor ALL at the age of 6 (Twin 1, T1) and 6.5 years (T2). The diagnostic and relapse samples showed common and unique lesions, allowing us to hypothesize a model for leukemia clonal evolution. At diagnosis, T1 had common ALL with 45,XX,-7,del(9)(p12),del(10)(q23)[8]/46,XX[12] whereas T2 had common ALL with 45,XX,-7,del(10)(q22)[14]. Both were treated according to AIEOP-BFM ALL 2000 protocol; T1 was classified as MRD high risk (HR), and T2 as MRD Intermediate risk (IR). T1 underwent BMT 8 months after diagnosis, and achieved clinical remission, still persisting, whilst T2 relapsed 13 months after diagnosis with 47,XX,del(9)(p21),+21[11]/46,XX[5]; she entered AIEOP REC 2003 protocol and, after achieving second complete remission and negativity for MRD, underwent allogeneic HLA-compatible BMT; she is in clinical remission 3.5 years after BMT. Results: Genome-wide copy number alteration (CNA) analysis by Cytogenetics Whole Genome 2.7M Arrays (Affymetrix) indicated that T1 and T2 shared a copy number neutral Loss Of Heterozygosity (LOH) of 17q arm, were the NF1 gene is located. At diagnosis, both had chromosome 7 monosomy but showed completely different Ig/TCR rearrangements. Three additional clonal rearrangements were found in T2 relapse sample. By backtracking the rearrangements, the relapse clone was detected in about 1% of T2 diagnostic cells, but not in T1 diagnosis sample. Several twin-specific abnormalities were detected: both had a deletion involving the q arm of chromosome 10, with different extent: del(10)(q23.33) in T1 and del(10)(q23.1) in T2. Moreover, T1 carried hemizygous deletions on chromosome 9 and a focal loss of 6q15 locus, containing the B-cell specific transcriptional regulator BACH2. Genomic analysis of T2 revealed a gain in the telomeric region of chromosome 2 and heterozygous losses in 14q32.13 and 15q21.3 regions, involving BX247990 (human full-length cDNA clone of B cells) and TCF12 (transcription factor 12) genes, respectively. The T2 relapse showed LOH 17q and del(15)(q21.3), as found in her diagnostic sample, and several additional CNAs, including the heterozygous deletions of IKZF1 (7p12.2), ETV6 (12p13.2) and C20orf94 (20p12.2) genes, trisomy of chromosome 21 and LOH of chromosome 20. Discussion: This is the first study that describes the natural history of events in NF1 patients (with 17q LOH) who developed ALL. The unique feature common to both twins in diagnosis and relapse samples was 17q LOH, that probably arose prenatally in a common hematopoietic progenitor (before somatic recombination) of one twin and spread to the other twin through intraplacental circulation. After birth, an independent clonal evolution is sustained by different Ig/TCR rearrangements as well as specific and different oncogenetic lesions. This model support a preleukemic state followed by at least-two-step mechanism for progression to leukemia. The absence of monosomy 7 at relapse indicates an independent and postnatal acquisition of this lesion; and that relapse in T2 occurs from a pre-leukemic clone before monosomy 7, which further evolved through acquisition of additional abnormailities, commom in BCP-ALL (i.e. ETV6 and Ikaros deletions). The role of BACH2 and TCF12 gene deletions in NF1 and ALL must be further explored. BACH2 is a human B-cell specific transcriptional repressor already described as tumor suppressor gene, involved in IgH@ translocations. TCF12 (also named HEB) is a basic helix-loop-helix transcription factor involved in B and T cell commitment. The altered expression of these genes could contribute to the differentiation arrest and the uncontrolled proliferation of leukemic blasts. Disclosures: No relevant conflicts of interest to declare.

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Kyriakidis, Ioannis, Konstantinos Kyriakidis et Aspasia Tsezou. « MicroRNAs and the Diagnosis of Childhood Acute Lymphoblastic Leukemia : Systematic Review, Meta-Analysis and Re-Analysis with Novel Small RNA-Seq Tools ». Cancers 14, n^o 16 (17 août 2022) : 3976. http://dx.doi.org/10.3390/cancers14163976.

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MicroRNAs (miRNAs) have been implicated in childhood acute lymphoblastic leukemia (ALL) pathogenesis. We performed a systematic review and meta-analysis of miRNA single-nucleotide polymorphisms (SNPs) in childhood ALL compared with healthy children, which revealed (i) that the CC genotype of rs4938723 in pri-miR-34b/c and the TT genotype of rs543412 in miR-100 confer protection against ALL occurrence in children; (ii) no significant association between rs2910164 genotypes in miR-146a and childhood ALL; and (iii) SNPs in DROSHA, miR-449b, miR-938, miR-3117 and miR-3689d-2 genes seem to be associated with susceptibility to B-ALL in childhood. A review of published literature on differential expression of miRNAs in children with ALL compared with controls revealed a significant upregulation of the miR-128 family, miR-130b, miR-155, miR-181 family, miR-210, miR-222, miR-363 and miR-708, along with significant downregulation of miR-143 and miR-148a, seem to have a definite role in childhood ALL development. MicroRNA signatures among childhood ALL subtypes, along with differential miRNA expression patterns between B-ALL and T-ALL cases, were scrutinized. With respect to T-ALL pediatric cases, we reanalyzed RNA-seq datasets with a robust and sensitive pipeline and confirmed the significant differential expression of hsa-miR-16-5p, hsa-miR-19b-3p, hsa-miR-92a-2-5p, hsa-miR-128-3p (ranked first), hsa-miR-130b-3p and -5p, hsa-miR-181a-5p, -2-3p and -3p, hsa-miR-181b-5p and -3p, hsa-miR-145-5p and hsa-miR-574-3p, as described in the literature, along with novel identified miRNAs.

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Moqadam, Farhad Akbari, Ellen Lange-Turenhout, Rob Pieters et Monique L. Den Boer. « Collaboration Between MiR-125b, MiR-100 and MiR-99a Induces Vincristine Resistance in Childhood TEL-AML1-Positive Acute Lymphoblastic Leukemia ». Blood 120, n^o 21 (16 novembre 2012) : 1475. http://dx.doi.org/10.1182/blood.v120.21.1475.1475.

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Abstract Abstract 1475 MicroRNAs (miRNAs) are involved in the pathobiology of leukemia. We previously observed that miR-125b, miR-99a and miR-100 were highly expressed in ex vivo vincristine (VCR) resistant leukemic cells of children with precursor B-cell acute lymphoblastic leukemia (ALL) (Schotte et al. Haematologica 2011). VCR is a microtubulin-interfering drug applied in the treatment of children with newly diagnosed ALL. Leukemic cells of TEL-AML1-positive precursor B-cell ALL were found to be resistant to this drug (Ramakers-van Woerden et al. Blood 2000). The expression levels of miR-125b, miR-99a and miR-100 were highly correlated in childhood precursor B-ALL cells. MiR-125b, as the most well-known miRNA among these three, was shown to contribute to drug resistance in different types of solid tumors. Down-regulation of miR-125b was also shown to sensitize the TEL-AML1-positive Reh cell line to doxorubicin and staurosporine (Gefen et al. Leukemia 2010). However, recent studies suggest that miRNAs co-operate and the combination of multiple distinct miRNAs co-regulates expression of associated target genes. The current study addressed whether miR-125b alone or in combination with miR-99a and/or miR-100 contributed to VCR resistance in childhood TEL-AML1-positive ALL cells. MiRNAs were over-expressed in TEL-AML1-positive Reh cells using lentiviral particles and/or miRNA precursors. Expression level of mature (and hence processed precursor) miRNAs was analyzed by qRT-PCR. The cell cycle distribution and the amount of leukemic cells in apoptosis were determined by flow cytometry of propidium iodide stained nuclei and Annexin V-propidium iodide stained cells, respectively. Leukemic cells were incubated with 9 ng/mL VCR and after 3 days of exposure the cellular response to VCR was measured by an MTT-based cell survival assay. The expression level of mature miR-125b, miR-99a and miR-100 was raised >100-fold upon lentiviral and precursor miRNA transduction compared to basal expression levels of TEL-AML1-positive Reh cells. Over-expression of miR-125b, miR-99a or miR-100 as single miRNAs did not significantly affect cellular survival after 3 days of exposure to VCR (20±5%, 29±17% and 29±17% viable cells, respectively) compared to the cells transduced with a scrambled miR-control (10±4% viable cells, p>0.05 each) when cell viability in absence of VCR was set to 100%. Over-expression of the combination of miR-100 and miR-99a only had a limited protective effect on cell viability (30±7% viable cells compared to 10±4% viable cells for the scrambled miR-control, p<0.05). In contrast, co-expression of miR-99a or miR-100 together with miR-125b or the combination of miR-99a and miR-100 together with miR-125b strongly and significantly induced resistance to VCR in TEL-AML- positive Reh cells; 91±4% of miR-99a/miR-125b-transduced, 93±5% of miR-100/miR-125b-transduced and 82±17% of miR-99a/miR-100/miR-125b-transduced cells remained alive upon VCR exposure compared to only 38±13% of miR-125b-transduced cells (p<0.05). The combination of these miRNAs did not change the cell cycle distribution or the amount of apoptotic cells in the absence of VCR. This suggests that these 3 miRNAs synergize in the development of resistance to VCR. Computational miRNA target prediction algorithms (TargetScan and EIMMo3) predicted 14 possible protein-coding target genes for the combination of miR-125b, miR-99a and miR-100. Gene expression profiling of ex vivo VCR-resistant (n=20) and VCR-sensitive (n=10) leukemic cells of TEL-AML1-positive ALL patients revealed that the expression levels of these 14 predicted target genes did not differ between resistant and sensitive cases (p>0.05). Ongoing studies currently explore which other protein-coding genes can be directly targeted by the miR125b, miR-99a and/or miR100 combination using functional gene expression studies. In conclusion, miR-125b, miR-99a or miR-100 as single factors were not effective to induce VCR resistance. In contrast, miR-125b in combination with miR-99a and/or miR-100 strongly increased VCR resistance in leukemic cells of TEL-AML1-positive precursor B-ALL. Discovery of directly regulated protein-coding target genes of these 3 miRNAs may point to ways to modulate resistance to VCR in children with ALL. Disclosures: No relevant conflicts of interest to declare.

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Domizi, Pablo, Jolanda Sarno, Astraea Jager, Reema Baskar, Warren D. Reynolds, Bita Sahaf, Sean Bendall et al. « Ikaros Mediates Antigen Escape Following CD19 CAR T Cell Therapy in r/r B-ALL ». Blood 138, Supplement 1 (5 novembre 2021) : 613. http://dx.doi.org/10.1182/blood-2021-151002.

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Abstract Despite impressive response to front-line treatment, relapsed or refractory B-cell acute lymphoblastic leukemia (r/r B-ALL) remains one of the most common causes of death in children with cancer. In pediatric and adult r/r B-ALL, CD19 CAR T cell (CART19) therapy has shown impressive results with over 80% of patients achieving complete remission. However, as an unintended consequence of long-term persistence of CAR T cells and the resulting sustained pressure against CD19 expressing cells, 30 - 70% of initial responders will eventually relapse with CD19 loss. Early identification of patients that will respond successfully to CART19 therapy vs. those at risk for CD19 Neg relapse would support clinical decision making and improve patient care. To address this problem, we profiled by mass cytometry (CyTOF) 25 pre-CART19 samples including patients that achieved a durable complete remission (CR, n = 6), patients that underwent CD19 Neg (n = 11) or CD19 Pos relapse (n = 4) and patients that were refractory to CART19 (n = 4). For 14 of those patients, we also analyzed paired post-CART19 samples: 8 from CD19 Neg relapse, 2 from CD19 Pos relapse, and 4 from refractory tumors. We observed a significant increase in the proportion of leukemic early progenitor non-B cells (called early-non-BI) after CD19 Neg relapse, suggesting that CD19 loss is associated with the loss of other B cell features. In addition, in the pre-CART19 samples we identified a subpopulation of CD19 Pos pro-B cells that resemble early-non-BI cells. We hypothesized that these pro-B "discordant" cells are able to lose CD19 expression and escape the immune pressure exerted by the CART19, leading to CD19 Neg relapse. Closer analysis revealed lower levels of IKAROS in pro-B discordant cells from patients that underwent CD19 Neg relapse, than in those that achieved a durable CR. To further explore the difference between pro-B discordant cells from patients that achieved a durable CR or underwent CD19 Neg relapse, we performed single cell REAP-seq (RNA expression and protein sequencing) from 3 pre-CART19 CR and 3 pre-CART19 CD19 Neg relapse r/r B-ALL samples. From this analysis, we confirmed a subpopulation of leukemic pro-B like cells with decreased expression of IKZF1 in those patients that underwent CD19 Neg relapse. IKAROS is a transcription factor that plays a crucial role in B cell lineage specification and commitment and is a known B-ALL tumor suppressor. Genetic alterations affecting the IKAROS gene, IKZF1, have been associated with poor response to front-line treatment and they are a factor in relapse risk stratification. However, a role for IKAROS in CART19 failure has not been described. To assess if there is a correlation between the levels of IKAROS and CD19 surface expression, we manipulated IKAROS levels in B-ALL cell lines through RNA silencing and targeted protein degradation approaches. Consistently, we observed that CD19 surface expression diminishes upon IKAROS downregulation. To determine how IKAROS regulates CD19 expression, we performed CyTOF, RNA-seq and ATAC-seq analysis of isogenic B-ALL cell lines with wild-type or reduced (IKAROS KD) IKAROS levels. While the chromatin accessibility to CD19 regulatory regions did not change, CD19 mRNA levels were lower in IKAROS KD cells. Interestingly, we found that IKAROS regulates several genes associated with mRNA splicing. In particular, CD19 mRNA preferentially retains intron 10 in IKAROS KD cells. The inclusion of intron 10 introduces several premature stop codons. Moreover, IKAROS KD B-ALL cells more closely resemble myeloid cells based on their gene expression profiles, suggesting a loss in their B cell identity. In summary, this is the first description of a leukemia-specific subpopulation of CD19 Pos pro-B discordant cells in patients prior CART19 administration. Furthermore, lower levels of IKAROS in this subpopulation correlates with poor response to CART19 therapy. Preliminary molecular analysis suggests that low IKAROS result in retention of CD19 intron 10 and loss of B-cell identity (Figure 1). Future research will focus on in-depth characterization of the myeloid-like phenotype induced by low levels of IKAROS expression, and the impact that intron 10 retention has on CD19 mRNA stability and surface expression. Figure 1 Figure 1. Disclosures Mullighan: Pfizer: Research Funding; Amgen: Current equity holder in publicly-traded company; Illumina: Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding. Grupp: Novartis, Roche, GSK, Humanigen, CBMG, Eureka, and Janssen/JnJ: Consultancy; Novartis, Adaptimmune, TCR2, Cellectis, Juno, Vertex, Allogene and Cabaletta: Other: Study steering committees or scientific advisory boards; Novartis, Kite, Vertex, and Servier: Research Funding; Jazz Pharmaceuticals: Consultancy, Other: Steering committee, Research Funding. Barrett: Tmunity Therapeutics: Current Employment. Davis: Novartis Pharmaceuticals: Honoraria; Jazz Pharmaceuticals: Research Funding.

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Lechman, Eric R., Karin G. Hermans, Stephanie M. Dobson, Olga I. Gan, James A. Kennedy, John Chen, Johann K. Hitzler et John E. Dick. « Modeling the Multi-Step Pathogenesis of Acute Myeloid Leukemia of Down Syndrome ». Blood 124, n^o 21 (6 décembre 2014) : 3579. http://dx.doi.org/10.1182/blood.v124.21.3579.3579.

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Abstract The multistep pathogenesis of Down Syndrome (DS)-associated pre-leukemia and subsequent progression to acute leukemia is one of the better characterized of all human blood malignancies. Children with DS have a 150 fold increased risk of developing acute megakaryoblastic leukemia (AMKL) and greater than 30 fold increased risk of developing B cell acute lymphoblastic leukemia (B-ALL). DS-AMKL is often preceded in late fetal development or soon after birth by a pre-leukemic syndrome termed transient myeloproliferative disorder (TMD), which is characterized by high numbers of abnormal megakaryocytes and megakaryoblasts in the circulation, spleen and liver. Previous work has demonstrated that constitutional trisomy 21 results in expansion of megakaryocyte-erythroid progenitors (MEP) in fetal liver (FL) with a concomitant reduction in fetal pre-pro-B cells. The expanded MEP population subsequently acquires an N-terminal truncating mutation in the transcription factor GATA1 (termed GATA1s), leading to selective expansion of a pre-leukemic erythromegakaryocytic blast population. While the majority of DS-TMD cases spontaneously resolve within 3 months, up to 15% of DS-TMD neonates can develop lethal progressive liver fibrosis. Progression to AMKL following spontaneous resolution of TMD is associated with acquisition of at least one additional germline mutation. While murine models implicate a role for trisomy 21 and GATA1s in the leukemogenic process, they do not faithfully recapitulate the pathology of the human disease. Previous attempts to model DS-associated TMD through xenotransplantation of DS-FL and DS-TMD cells have proven technically challenging. Therefore, there remains a need for a human model to investigate the genetic steps required for initiation of DS-TMD and progression to DS-AMKL. We previously identified a leukemia stem cell (LSC)-associated miRNA signature by sorting 13 adult AML patient samples into 4 sub-populations based on CD34/CD38 expression, followed by supervised analysis guided by the in vivo leukemia initiating capacity of each sub-population in an optimized xenotransplant model. Interestingly, the top three LSC-associated miRNA candidates are all located on chromosome 21. To determine the role of these miRNA in human leukemogenesis, we engineered a tri-cistronic lentivector for enforced expression. Compared to control vector-transduced cells, tri-cistronic vector-transduced Lin‒CD34+CD38‒ cord blood (CB) cells generated a myeloproliferative syndrome in xenotransplanted mice, with splenomegaly, enhanced CD45+ human bone marrow cellularity and blocked B cell development at the pro B cell stage. Human grafts were enriched for CD45+CD33+CD117+CD123+CD41lo/CD42lo cells in bone marrow, peripheral blood, spleen and liver. In the CD45‒ compartment, a distinct lineage switch was observed, with CD41+ megakaryocytic output supplanting normal CD235+ erythroid output. High numbers of CD41+CD42b+CD61+CD34lo human platelets were detected in peripheral blood and spleen. Blood films revealed large dysplastic platelets and megakaryoblast-like cells. Histology showed hCD45+ packed bone marrow cavities, with loss of normal architecture. Bone marrow, spleen and liver all showed extensive reticulin deposition. In the lineage negative (Lin-) fraction of BM, we observed an expansion in the proportion of human MEP and multi-lymphoid progenitors (MLP). To further model leukemic progression, we expressed GATA1s in combination with our tri-cistronic miRNA vector. Mice transplanted with double transduced cells showed intermediate levels of splenomegaly and bone marrow cellularity compared to mice transplanted with cells transduced with tri-cistronic vector alone. The addition of GATA1s induced a complete loss of B cell development while restoring erythroid development. In human Lin‒ cells isolated from the BM, addition of mutant GATA1s further augmented the proportion and total numbers of MEP while restoring the MLP compartment to normal levels. These data demonstrate that we have generated a human xenograft model of DS-TMD through enforced expression in normal CB cells of a tri-cistron comprising 3 LSC-associated miRNA in combination with mutant GATA1s. With this model in place, we plan to further interrogate the genetic lesions involved in progression from DS-TMD to DS-AMKL. Disclosures No relevant conflicts of interest to declare.

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de Rooij, Jasmijn, Eva Beuling, C. Michel Zwaan, Askar Obulkasim, André Baruchel, Jan Trka, Dirk Reinhardt et al. « IKZF1 deletions in Pediatric Acute Myeloid Leukemia ». Blood 124, n^o 21 (6 décembre 2014) : 2346. http://dx.doi.org/10.1182/blood.v124.21.2346.2346.

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Abstract IKAROS family zinc finger 1 (IKZF1) is a transcription factor involved in lymphoid differentiation that acts as a tumor suppressor. In B-cell precursor acute lymphoblastic leukemia (BCP-ALL) loss of IKZF1 is found in ~15% of the patients, is associated with the presence of BCR/ABL1 (t(9;22)(q34;q11)) and confers a poor clinical outcome. Recent studies suggest that IKZF1 is also involved in myeloid differentiation. The best indication that loss of IKZF1 may contribute to myeloid leukemogenesis are deletions of the short arm of chromosome 7 associated with myeloproliferative-preceded secondary acute myeloid leukemia (AML) in adults, where the commonly deleted region is mapped to the IKZF1 locus (Jager et al,Leukemia 2010). To investigate whether IKZF1 deletions play a role in pediatric AML we screened a representative well-characterized panel of 258 de novo pediatric AML samples with available gene expression data, obtained from the DCOG (The Hague, the Netherlands), the AML–Berliner-Frankfurt-Münster Study Group (Germany and Czech Republic), the Saint-Louis Hospital (Paris, France) and the Royal Hospital for Sick Children (Glasgow, UK) for deletions of the IKZF1 locus on chromosome 7p12.2 using multiplex ligation-dependent probe amplification (MLPA). Median age of the patients was 9.5 years (range 0.1-18.5 years), median white blood cell count was 46.7x109/L (range 1.2-483x109/L). All major cytogenetic subgroups were included and all patients had received intensive cytarabine-anthracycline based pediatric AML therapy. Of 11 patients with an IKZF1 deletion, 8 cases presented with monosomy 7, and 3 cases showed a focal deletion of IKZF1. These focal deletions included the complete IKZF1 gene (n=2) or exons 1-4 (n=1), leading to a loss of IKZF1 function. Focal deletions were confirmed by high-resolution array comparative genome hybridization (array-CGH). Patients with a focal deletion included a 1.5 year old boy diagnosed with AML with a fusion of MNX1/ETV6 who died from relapse; an 11.3 year old girl diagnosed with AML M5 who remains in continuous complete remission (CCR) after salvage therapy for relapse; and a 2.3 year old boy diagnosed with AML M5 in CCR. IKZF1 deleted cases (n=11) did not differ significantly from the other pediatric AML cases (n=247) with regards to age at diagnosis (median age 9.1 years compared to 9.5 years respectively, p=0.41); gender (females 55% versus 42%, p=0.41); or white blood cell count at diagnosis (median 30.2 x109/L versus 47.5 x109/L, p=0.24). No specific FAB morphology subtypes were related to IKZF1 deletions. IKZF1 deleted samples showed either none or various different additional somatic mutations, most frequently activating the RAS pathway with mutations in NRAS or PTPN11 (n=4,). In BCP-ALL IKZF1 deletions are associated with BCR/ABL1 fusions and to test if this was also true for IKZF1 deletions in AML we screened samples for the BCR/ABL1 fusion and all were negative. The 3-year pOS in IKZF1 deleted patients (n=11) was 70±14% versus 63±3% (p=0.82) in IKZF1 wild-type patients (n=231). The 3-year pEFS was 36±15% versus 46±3%, and the 3-year pCIR was 64±16% versus 36±3% (p=0.87 and p=0.09) respectively. Genes differentially expressed in monosomy 7 cases correlated significantly with gene expression changes in focal IKZF1 deleted cases when comparing significant differences to non-IKZF1-deleted cases (n=247). Genes showing increased expression in IKZF1 deleted samples included those involved in myeloid cell cycling and self-renewal, such as HEMGN, FHL2, FZD6, and SETBP1. In summary, we found focal IKZF1 deletions to be rare but recurrent events in pediatric AML. Gene expression patterns suggest that the loss of IKZF1 may be an important determinant in the biology of pediatric AML with monosomy 7. Disclosures No relevant conflicts of interest to declare.

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Kuiper, Roland P., Esmee Waanders, Vincent H. J. Van der Velden, Simon V. van Reijmersdal, Blanca Scheijen, Jayne Hehir-Kwa, Suzanne T. M. Keijzers-Vloet et al. « Deletion of IKZF1 in Pediatric Precursor-B ALL Is a Strong Prognostic Marker for Relapse. » Blood 114, n^o 22 (20 novembre 2009) : 1104. http://dx.doi.org/10.1182/blood.v114.22.1104.1104.

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Abstract Abstract 1104 Poster Board I-126 Relapse is the most common cause of treatment failure in pediatric acute lymphoblastic leukemia (ALL), and is difficult to predict from information at diagnosis in the majority of cases. To explore the prognostic impact of recurrent copy number abnormalities on relapse in children diagnosed with precursor-B cell ALL, we performed genome-wide copy number profiling of 34 paired diagnosis-relapse samples. Lesions detected at diagnosis were often absent at relapse, including recurrent targets in precursor-B ALL like PAX5 (not preserved in 2 out of 7 cases with deletions at diagnosis), CDKN2A (not preserved in 1 out of 15 cases), and EBF (not preserved in 2 out of 5 cases), which illustrates that these lesions are often secondary events that are not present in the therapy-resistant progenitor that causes relapse. In contrast, deletions and nonsense mutations in IKZF1, which encodes the lymphoid differentiation factor IKAROS, were highly frequent (38%) and always preserved at time of relapse. Locus-specific copy number screening of IKZF1 in an additional cohort of diagnosis samples from children enrolled in the Dutch treatment protocol DCOG-ALL9 with (n=40) or without (n=51) relapse revealed that IKZF1 deletions were significantly enriched in relapse-prone cases (22.5% vs 3.9%; P=0.007). An independent and unbiased validation cohort of 150 DCOG-ALL9 cases was used to confirm these findings, which established that 28.6% of the cases with IKZF1 deletion at diagnosis developed a relapse. Together, we conclude that deletions of IKZF1 in DCOG-ALL9 treated pediatric precursor-B ALL patients provide a strong prognostic marker for relapse. Disclosures No relevant conflicts of interest to declare.

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Joshi, Ila, Nilamani Jena, Toshimi Yoshida, Leto Paraskevopoulou, Zhihong Zhang, Zhong-Ying Liu, Shane Korber et al. « Focal Adhesion Kinase Inhibitors Reverse the Stromal Adhesion Phenotype of Ikaros-Mutant B-ALL, Induce Apopotosis, and Synergize with ABL1 Tyrosine Kinase Inhibitors : A New Paradigm for Pathogenesis and Therapy of High-Risk B-ALL ». Blood 124, n^o 21 (6 décembre 2014) : 285. http://dx.doi.org/10.1182/blood.v124.21.285.285.

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Abstract B-cell acute lymphoblastic leukemia (B-ALL) is a malignancy of precursor B-lymphocytes affecting both children and adults. Deletions and dominant-negative mutations in IKZF1, the gene encoding the Ikaros transcription factor, are found in ~85% of Ph+ B-ALL and in some cases of Ph– B-ALL, and are associated with poor prognosis. Genomic studies of high-risk Ph– or “Ph-like” B-ALLs have revealed frequent mutation and activation of TK genes and signaling pathways. While ABL1 tyrosine kinase inhibitors (TKIs) such as dasatinib and imatinib have been added to chemotherapy regimens for Ph+ B-ALL, over half of these patients will still relapse, which correlates with residual disease burden in the bone marrow (BM) following induction therapy. Hence, new therapeutic strategies are needed for patients with Ikaros-mutant, high-risk Ph+ and Ph– B-ALL. Using mice with a conditional Ikzf1 mutation (Ike5fl) where the recombined allele is similar to the dominant-negative Ik6 mutant found in human B-ALL, we demonstrated recently that Ikaros DNA-binding function is required in the B-lymphoid lineage for transition from the large to small pre-B cell stage of differentiation, and that arrest at this stage of development can give rise to B-ALL (Joshi et al., Nat. Immunol. 2014;15:294). The survival and proliferation of Ikaros mutant pre-B cells is dependent on increased integrin-mediated stromal adhesion and activation of focal adhesion kinase (FAK). FAK is a non-receptor TK, downstream of integrins and growth factor receptors, which plays important roles in cancer stem cell biology, the tumor microenvironment and tumorigenesis. VS-4718 and VS-6063 (defactinib) are potent, orally bioavailable FAK inhibitors that inhibit tumor growth and metastasis in preclinical models, and are currently under evaluation in clinical trials in patients with various solid tumors. VS-6063 has demonstrated tolerability and preliminary signs of clinical activity as a single agent and in combination with paclitaxel in phase I trials (ASCO, 2014). Here, we show that BCR-ABL1 cooperates with Ikzf1 mutation to accelerate B-leukemogenesis in mice. BCR-ABL1+ Ikaros-mutant B-ALLs exhibit stroma-mediated resistance to ABL1 TKIs, while the FAK inhibitors VS-4718 and VS-6063 are effective in blocking stromal adhesion and inducing apoptosis in both mouse and human Ikaros-mutant B-ALL samples. To test whether dysregulation of TK signaling cooperates with Ikzf1 mutation in the pathogenesis of high-risk B-ALL, we isolated BM B-lymphoid progenitor cells from wild-type (WT), IkE5fl/+ CD2-Cre, and IkE5fl/fl CD2-Cre donors, transduced them with BCR-ABL1 retrovirus and transplanted the cells into recipient mice. We observed a dramatic acceleration of precursor B-lymphoid leukemia induced by BCR-ABL1 in IkE5Δ/+ and particularly in IkE5Δ/Δ donor cells that correlated with a striking (~30-fold) increase in the frequency of engrafting leukemia-initiating or leukemic stem cells (LSCs). Relative to Ikzf1 WT BCR-ABL1+ leukemic cells, Ikzf1-mutant BCR-ABL1+ blasts showed significant resistance to imatinib and dasatinib that was dependent on the presence of OP9 stroma. The effect of FAK inhibition, using the FAK inhibitors VS-4718, VS-6062, and VS-6063 (Verastem), was first tested on murine B-ALL cells (genotypes Ikzf1 mutant, Ikzf1 mutant BCR-ABL1+, and Ikzf1 WT BCR-ABL1+) grown on OP9 stroma. FAK inhibitor treatment abolished stromal adhesion of Ikzf1-mutant B-ALL and induced apoptosis in non-adherent cells, but had little effect on Ikzf1 WT B-ALL cells. VS-4718 and VS-6063 were each synergistic with dasatinib in reducing the viability of Ikzf1-mutant BCR-ABL1+ B-ALL cells cultured on OP9 stroma. For primary human B-ALL samples grown on OP9 stroma, IKZF1-mutant cells were also more sensitive to FAK inhibitor treatment than WT IKZF1 WT B-ALL, with or without BCR-ABL1 expression. Collectively, these observations suggest a new model to explain the pathogenesis of high-risk B-ALL and its resistance to therapy. B-ALLs with IKZF1 mutations may be resistant to TKIs and to chemotherapy by virtue of their stromal adhesion phenotype, resulting in failure to eliminate BM LSCs. Inhibition of FAK signaling in Ph+ or Ph–IKZF1-mutant B-ALL may reverse the stromal-mediated resistance to ABL1 TKIs and/or chemotherapy. Therefore, FAK inhibitors warrant further investigation for the treatment of high-risk IKZF1-mutant B-ALL patients. Disclosures Joshi: Verastem: Research Funding. Yoshida:Verastem, Inc.: Research Funding. Paraskevopoulou:Verastem, Inc.: Research Funding. Zhang:Verastem, Inc.: Research Funding. Krause:Glycomimetics. Inc.: Research Funding. Shapiro:Verastem: Employment, Equity Ownership. Weaver:Verastem: Employment, Equity Ownership. Pachter:Verastem Inc.: Employment, Equity Ownership. Georgopoulos:Verastem, Inc.: Research Funding.

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Akbari Moqadam, Farhad, Judith M. Boer, Ellen Lange-Turenhout, Rob Pieters et Monique L. Den Boer. « Enforced Expression Of MiR-24, MiR-126 and MiR-365 Does Not Alter Cellular Viability In TCF3-Rearranged Leukemia ». Blood 122, n^o 21 (15 novembre 2013) : 2630. http://dx.doi.org/10.1182/blood.v122.21.2630.2630.

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Abstract MicroRNAs (miRNAs) are involved in fine-tuning of the several cellular processes in human healthy and malignant tissues. In various types of tumors, miR-24, miR-126 and miR-365 were shown to regulate cell cycle progression and apoptosis. Interestingly, these three miRNAs were downregulated in pediatric TCF3-rearranged B-cell precursor acute lymphoblastic leukemia (BCP-ALL) (Schotte et al. Haematologica 2011). Here, we investigated whether these three miRNAs, individually or in combination, may alter cell cycle distribution and amount of apoptosis in TCF3-rearranged leukemia. In addition, we used a new miRNA target identification method (van Iterson et al. Nucleic Acid Res 2013) which integrates the mRNA and miRNA expression profiles of 37 cases with childhood BCP-ALL (4 BCR-ABL1-positive, 3 TCF3-rearranged, 7 ETV6-RUNX1-positive, 13 hyperdiploid (>50 chromosomes) and 10 unclassified B-others negative for the above mentioned genetic aberrations). Following overexpression of miRNAs in TCF3-rearranged leukemic cells, changes in the expression levels of predicted candidate target genes in our miRNA-mRNA integration cohort were analyzed to discover functional relationships between these miRNAs and their predicted candidate target genes in BCP-ALL. MiRNAs were over-expressed in three TCF3-rearranged leukemic cells; i.e. 697, KASUMI-2 and MHH-CALL-3 cells, using miRNA precursors transfection. Expression level of mature miRNAs and candidate target genes were analyzed by qRT-PCR. The cell cycle distribution and the amount of leukemic cells in apoptosis were determined by flow cytometry of propidium iodide stained nuclei and Annexin V-propidium iodide stained cells, respectively. Our data revealed that the expression level of mature miR-24, miR-126 and miR-365 was raised >100-fold upon precursor miRNA transduction compared to basal expression levels of Three TCF3-rearranged leukemic cell lines. Individual or combined overexpression of miR-24, miR-126 and miR-365 did not alter cell cycle progression and amount of apoptosis in these three different leukemic cell lines. Integration of miRNA and mRNA expression levels of 37 newly diagnosed children with BCP-ALL revealed significant association between the expression of 29 miRNAs and their predicted target genes (FDR<0.05, p<0.005), including miR-24 (ranked at position #5), miR-126 (ranked at position #17) and miR-365 (ranked at position #20). Candidate target genes were selected for further analysis: ELL, EBF3 and IRF4 for miR-24 (Pearson r <-0.6, p<0.005), PITPNC1 for miR-126 (Pearson r <-0.5, p<0.01) and ZAP-70 for miR-365 (Pearson r <-0.4, p<0.01). However, miRNAs overexpression in MHH-CALL-3 cells did not reduce the expression levels of these selected candidate target genes. Considering the presence of only 3 patients with TCF3-rearranged ALL in our miRNA-mRNA expression data integration cohort, the observed significant inverse correlation between miRNA-mRNA pairs might mainly originate from other subtypes with higher number of cases in this cohort, such as hyperdiploid (13 cases) or unclassified B-others BCP-ALL (10 cases). Interestingly, expression level of AURKB – a validated target for miR-24 – was reduced by ∼4-fold upon miR-24 overexpression in hepatocarcinoma HEP-G2 cells, while overexpression of similar amount of miR-24 cannot alter AURKB expression levels in MHH-CALL-3 leukemic cells. Together, our findings indicate that individual and combined expression of miR-24, miR-126 and/or miR-365 does not affect the amount of apoptosis and cell cycle distribution in TCF3-rearranged leukemia. Moreover, our data suggest that miRNAs function is highly cell type-dependent and a defined biological target gene or function of one miRNA in a specific cellular context cannot be generalized for all types of cells/tissues. Disclosures: No relevant conflicts of interest to declare.

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Kuiper, Roland P., Frank N. van Leeuwen, Suzanne T. M. Keijzers-Vloet, Simon V. van Reijmersdal, Jayne Y. Hehir-Kwa, Elisabeth R. van Wering, Vincent H. J. van der Velden et al. « Detection of Genomic Lesions in Childhood Precursor-B Cell ALL in Diagnosis and Relapse Samples Using High Resolution Genomic Profiling. » Blood 110, n^o 11 (16 novembre 2007) : 995. http://dx.doi.org/10.1182/blood.v110.11.995.995.

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Abstract Due to advances in therapeutic regimens developed during the last two decades, the majority of children with acute lymphoblastic leukemia (ALL) respond well to therapy. However, in approximately 25% of the patients relapses occur. Chomosome aneuploidies and recurrent chromosomal translocations are of considerable prognostic importance, and are routinely used in the course of clinical decision making. Current technological developments in molecular cytogenetic techniques have revealed that genetic lesions driving tumorigenesis frequently occur at the submicroscopic level and, consequently, escape standard cytogenetic observations. Therefore, we have previously performed high resolution genomic profiling of precursor-B-cell ALL samples obtained at diagnosis, using 250k NspI SNP-based oligoarrays from Affymetrix (Kuiper et al., 2007). By doing so, we detected multiple de novo genetic lesions, some of which were subtle and affected single genes. Many of these lesions involved recurrent (partially) overlapping deletions and duplications, encompassing various established leukemia-associated genes, such as ETV6, RUNX1, and MLL. Importantly, the most frequently affected genes were those controlling G1/S cell cycle progression (e.g. CDKN2A, CDKN1B, and RB1), followed by genes associated with B-cell development. The latter group included the B-lineage transcription factors PAX5, EBF, E2-2, and IKZF1 (Ikaros), as well as genes with other established roles in B-cell development, i.e., RAG1 and RAG2, FYN, PBEF1, or CBP/PAG. Here we have selected 34 additional precursor-B cell ALL cases that suffered from relapses 6 months to 9 years after diagnosis. Lesions affecting genes involved in G1/S cell cycle progression and B-cell development were observed with similar frequencies in the diagnosis and relapse samples as compared to our previous cohort of patients with unknown therapy response. However, additional (secondary) lesions were observed in the relapse samples in nearly all patients analyzed, indicating that these relapse samples are genomically distinct. In addition, several cases were encountered in which the diagnosis and relapse samples carried alternative lesions affecting the same gene(s), including CDKN2A and PAX5, suggesting that inactivation of these genes were secondary but essential events required to develop a full blown leukemia.

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Domizi, Pablo, Astraea Jager, Jolanda Sarno, Charles G. Mullighan, Stephan Grupp, Elena Sotillo, David M. Barrett et Kara L. Davis. « Prediction of Patients at Risk of CD19Neg Relapse Following CD19-Directed CAR T Cell Therapy in B Cell Precursor Acute Lymphoblastic Leukemia ». Blood 134, Supplement_1 (13 novembre 2019) : 749. http://dx.doi.org/10.1182/blood-2019-128883.

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CD19-directed chimeric antigen receptor T cell (CAR-T) therapy has shown impressive results in children and adults with relapsed or refractory B-ALL or diffuse large B-cell lymphoma. However, 30 - 70% of initial responders will eventually relapse with CD19 antigen loss (CD19Neg) (Maude SL, et al. N Engl J Med. 2018). To avoid CD19Neg relapse, patients may undergo a hematopoietic stem cell transplant (HSCT). HSCT is an expensive and often morbid procedure that many physicians would prefer to avoid. The development of tools to accurately predict which patients are at risk for CD19Neg relapse would guide treatment decisions regarding HSCT or alternative therapies. Since CD19Neg relapses also occur in patients treated with other CD19-directed immunotherapies, like blinatumomab (Mejstríková E, et al. Blood Cancer J. 2017), a predictive model to detect patients at risk of CD19Neg relapse would have broader therapeutic impact. To address this problem, we performed CyTOF and RNA-seq analysis from paired patient samples collected before CD19-directed CAR-T administration and after CD19Neg relapse. High dimensional phenotyping by CyTOF clustered patient samples based on their mechanism of CD19 expression loss (frameshift mutation versus expression of intracellular isoforms), even before CAR-T administration. In addition, we identified identical immunoglobulin heavy and light chain RNA sequences before CAR-T administration and after CD19Neg relapse, suggesting that the clones destined to cause relapse are present at the time of CAR-T administration. Altogether, these results support our hypothesis that resistant tumor cells are present before CAR-T administration and could be discovered and interrogated for CD19Neg relapse prediction. To identify cell subpopulations responsible for driving CD19Neg relapse, we used the B cell developmental classifier previously developed in our lab (Good Z, et al. Nat Med. 2018). We observed a significant increase in the Early-non-BI population (CD38Pos CD24Pos CD19Neg CD20Neg CD3Neg CD16Neg CD61Neg cells) after CD19Neg relapse, suggesting that CD19 loss is associated with the loss of other B cell features. Since our classifier relies on CD19 to classify cells, we compared the resulting classification of cells when CD19 was included or excluded in the classifier. This change had minimal impact in cell classification from healthy bone marrow controls. However, when applied to the samples collected before CAR-T administration, we found a subpopulation of CD19Pos Pro-B cells that classified as Early-non-BI cells when CD19 was excluded from the classification. We hypothesize that these Pro-B "discordant" cells are those that lose CD19 expression to escape the immune pressure exerted by the CD19-directed CAR-T and mediate CD19Neg relapse. Further, we found Pro-B "discordant" cells in 77% of independent cohort of 22 B-ALL samples collected at the time of diagnosis, suggesting these cells exist in de novo B-ALL. We likewise identified a CD19Neg IgMPos Early-non-BI subpopulation in 4 healthy bone marrow and further studies are ongoing to characterize these cells. We continue to interrogate this candidate population as that responsible for CD19Neg relapse after CAR-T cell therapy. In addition, we performed differential expression analysis between paired samples collected before (CD19Pos) and after (CD19Neg) CAR-T therapy. Through the application of the developmental classifier, we identified that CD19 loss is associated with upregulation of key B cell transcription factors IKAROS, PAX5 and glucocorticoid receptor in the pre-pro-B to Pre-B stages. Moreover, after CD19 loss, there are also increases in levels of phosphorylated proteins pSYK, pSRC and pSTAT5, involved in IL7 receptor and pre-BCR signaling pathways, essential for B cell development. This suggests that CD19Neg cells activate unique tumorigenic pathways that may provide novel therapeutic opportunities. Exploration and validation of these therapeutic targets could significantly improve clinical outcome and care of patients with CD19Neg B-ALL. In conclusion, these results support the feasibility to predict patients at risk for CD19Neg relapse together with the mechanism behind it. Future studies will be conducted to confirm unique tumorigenic pathways in CD19Neg B cells and determine their therapeutic potential. Disclosures Mullighan: Illumina: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: sponsored travel; Amgen: Honoraria, Other: speaker, sponsored travel; AbbVie: Research Funding; Pfizer: Honoraria, Other: speaker, sponsored travel, Research Funding; Loxo Oncology: Research Funding. Grupp:Humanigen: Consultancy; CBMG: Consultancy; Novartis: Consultancy, Research Funding; Roche: Consultancy; GSK: Consultancy; Novartis: Research Funding; Kite: Research Funding; Servier: Research Funding; Jazz: Other: study steering committees or scientific advisory boards; Adaptimmune: Other: study steering committees or scientific advisory boards; Cure Genetics: Consultancy.

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Russell, Lisa J., Melania Capasso, Inga Vater, Anthony V. Moorman, Takashi Akasaka, Lana Harder, Olaf Heidenreich et al. « IGH@ Translocations Involving the Pseudoautosomal Region 1 (PAR1) of Both Sex Chromosomes Deregulate the Cytokine Receptor-Like Factor 2 (CRLF2) Gene in B Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL) ». Blood 112, n^o 11 (16 novembre 2008) : 787. http://dx.doi.org/10.1182/blood.v112.11.787.787.

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Abstract We have recently described recurrent IGH@ translocations in BCP-ALL, which result in deregulated expression of the translocated oncogene. We carried out screening for novel IGH@ translocations in BCP-ALL by fluorescence in situ hybridization (FISH) and identified two cryptic translocations involving PAR1 of either sex chromosomes in 29 patients: t(X;14)(p22;q32) (n=18) and t(Y;14)(p11;q32) (n=7) (X or Y unknown, n= 4) and 2 BCP-ALL cell lines with t(Y;14)(p11;q32). The median age of the patients was 18 years (range 4–76 years) and median WBC was 70 ×109/l (range 1–342). Follow-up data was available for 16 patients. Among 5 children diagnosed 1996–2001, 1 failed to remit, 1 suffered an early death and 3 relapsed (16m, 54m, and 64m post diagnosis). To date, all 5 children diagnosed 2004–2005 are in first continuing complete remission (CCR) after 33–46 months, suggesting an improved outcome on the current childhood ALL treatment trial. All 6 adults were diagnosed 2004–2006: 2 died within a year (1 in remission and 1 post transplant); 2 relapsed and died within 1 year and 2 are in 1st CCR after 20 and 36 months. These observations indicate a variable outcome among adults. Translocation breakpoint cloning from IGHJ by long distance inverse PCR and subsequent FISH mapping identified CRLF2, also known as thymic stromal-derived lymphopoietin receptor, at Xp22 and Yp11, to be juxtaposed to IGH@ in these translocations. Breakpoints were cloned in 11 patients and clustered between 2–27kb centromeric of the 3′ UTR of CRLF2. Expression levels of CRLF2, measured by qRT-PCR in 4 patients and the cell lines, was 500–6,500 fold higher than the control cohort of BCP-ALL patients without the translocation. This overexpression confirmed CRLF2 to be the target gene. CRLF2 and IL2RGC bind to IL7RA to form functional receptors for TSLP and IL7, respectively. However, neither IL2RGC nor IL7RA were aberrantly expressed. The presence of associated genomic copy number alterations was shown by array-based comparative genomic hybridization and FISH. As described for BCP-ALL in general, the significant changes included deletions of the B cell differentiation genes: PAX5 and IKAROS, as well as the cell cycle control gene, CDKN2A. The cell lines revealed some biochemical insights into the functional consequences of this translocation involving PAR1. Cell surface expression of CRLF2 was demonstrated, together with constitutive tyrosine phosphorylation of JAK2 and STAT5, the signaling intermediates of the classical JAK-STAT pathway. Further evidence of increased STAT5 activation came from retroviral infection of normal mouse fetal liver cells with human CRLF2, which sustained the proliferation of B-cell precursors in vitro. Conversely, initial studies of CRLF2 knockdown in the cell lines using shRNA demonstrated decreased proliferation. Together, these results show for the first time, the involvement of both sex chromosomes in an IGH@ translocation in leukemia, resulting in deregulated expression of CRLF2 and constitutive JAK-STAT activation. These data suggest CRLF2 as a potential therapeutic target in this subset of patients. Laboratories of MJSD, RS and CJH contributed equally to this work.

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Van der Meulen, Joni, Evelien Mets, Pieter Mestdagh, Peter Pipelers, Tom Taghon, David Camacho Trujillo, David Avran et al. « Regulatory Networks Governed by MicroRNAs in T-ALL Oncogenesis and Normal T-Cell Development ». Blood 118, n^o 21 (18 novembre 2011) : 1366. http://dx.doi.org/10.1182/blood.v118.21.1366.1366.

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Abstract Abstract 1366 T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of thymocytes affecting children, adolescents and adults. T-ALL is characterized by a differentiation arrest at specific stages of T-cell development, primarily originating from the ectopic expression of T-cell oncogenes. Based on the mutation status of these genes and mRNA profiles, at least 5 different molecular-cytogenetic subgroups have been delineated. In addition, genetic abnormalities affecting cell cycle, proliferation, survival and self-renewal are present in all T-ALL subgroups. In a recent study, we discovered five oncogenic microRNAs (miRNAs) co-regulating the expression of key tumor suppressor genes implicated in the pathogenesis of T-ALL (Mavrakis et al., Nature Genetics, 2011). In this study, we established the extended miRNAome (756 miRNAs) in a genetically well characterized T-ALL patient cohort (n=65), 20 T-ALL cell lines as well as 9 different subsets of sorted T-cell populations from 3 human donors in parallel to mRNA and gene copy number profiles thus allowing integrative data mining. Cross-comparison between the different datasets resulted in the identification of miRNAs with presumed function in normal T-cell development as well as novel candidate miRNAs in T-ALL pathogenesis. The candidates were validated in an independent patient series (n=50). To better understand our previously established miRNA-mRNA regulatory T-cell/T-ALL network, we performed miRNA-mRNA correlation analysis followed by gene set enrichment analysis in order to assign putative functions to the selected miRNAs (http://www.mirnabodymap.org/; Mestdagh et al., Nucleic Acids Research, in press). In addition, the regulatory network was consolidated and extended through identification of miRNAs targeting selected key T-ALL oncogenes and tumor suppressor genes using a robust high throughput 3'UTR screening assay. In conclusion, this study further details the regulatory networks controlling normal T-cell development and T-ALL oncogenesis. Disclosures: No relevant conflicts of interest to declare.

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Buitenkamp, Trudy, Marry M. van den Heuvel, Astrid A. Danen-van Oorschot, Valerie de Haas, Rob Pieters, Monique L. Den Boer et C. Michel Zwaan. « Deletions in B-Cell Development Genes in Down Syndrome ALL : IKAROS Causes Poor Outcome ». Blood 114, n^o 22 (20 novembre 2009) : 3963. http://dx.doi.org/10.1182/blood.v114.22.3963.3963.

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Abstract Abstract 3963 Poster Board III-899 Children with Down Syndrome (DS) have an increased risk of developing acute lymphoblastic leukemia (ALL). DS ALL patients differ in presenting characteristics from ALL patients without DS (non-DS ALL). Recent evidence suggests that a unique genetic event may characterize DS ALL, i.e. an activating mutation localized at R683 in the Janus Kinase 2 (JAK2) gene, which occurs in 18% of DS ALL cases, and differs from the JAK2 mutations that are typically found in Myeloproliferatieve diseases (Bercovich et al, The Lancet 2008). However, Mullighan et al. recently reported also JAK R683 mutations in non-DS high risk ALL (PNAS, 2009). Furthermore, we and others described deletions in B-cell development genes in high-risk ALL (Den Boer et al, Lancet Oncology 2009, and Mullighan, NEJM 2009). One of these genes, IKZF1, which encodes the lymphoid transcription factor IKAROS, was found to be an indicator of poor prognosis in this high-risk group. In the present study, we studied deletions in B-cell development genes in DS ALL, utilizing array-Comparative Genomic Hybridisation (array-CGH, 105K Agilent). Moreover, genomic DNA was PCR-amplified with specific primers to detect the isoform 6 of IKAROS, which consists of a deletion of exon 3-6 resulting in expression of a dominant-negative form of IKAROS, with intact homodimerization but reduced DNA-binding capacity. We used direct sequencing for mutation screening of the pseudo-kinase and kinase domains of JAK2. Of 34 DS ALL patients treated according to the DCOG treatment protocols samples were available. All 34 patients had B-cell precursor ALL. Median follow up time was 5.7 years (range 1.2 – 15.4 years).In total, 19/34 (56%) DS ALL patients had one or more deletions in B-cell development genes (Table 1). Affected genes included the transcription factors IKZF1 (41%, n=14), PAX5 (12%, n=4) and VPREB1 (18%, n=6). These aberrations were not mutually exclusive. No deletions were found in EBF1 and TCF3 (E2A). Deletions in the PAX5 gene were part of larger deletions (≥0.5 million bases), whereas the other genes were mainly affected by focal deletions (<0.5 million bases). In 10/14 cases with IKZF1 abnormalities, the Isoform 6 was detected, whereas in 4 patients the entire IKZF1 gene was deleted due to a larger deletion on chromosome 7p. There were 2 cases with hyperdiploidy and 2 with a TEL/AML rearrangement; 3 of them had a deletion in one of the named transcription factors. One DS patient with a Philadelphia chromosome had a focal deletion in IKZF1 resulting in isoform 6, as well as a deletion in PAX5 and VPREB1. JAK2 mutations were detected in 5/34 patients (15%). Only one of the JAK2 R683 mutated DS ALL patients had a deletion of IKZF. Patients with an IKZF1 deletion had a significantly worse outcome when compared to patients without IKZF1 deletion (pEFS 57% vs. 95%; p=0.005), pDFS (62% vs. 95%; p=0.01) and pOS (71% vs. 95%; p=0.04). For PAX5 deleted cases, the pOS was 50% vs. 90% in non-PAX5 deleted cases (p=0.03), but the differences for pEFS (50% vs. 83%; p=0.14) and pDFS (50.0% vs. 86%; p=0.06) were not significant. None of the JAK2 mutated patients had an event. Multivariate Cox regression analysis including age, WBC, JAK2, TEL/AML, IKZF1, PAX5 and VPREB1 showed that deletion of IKZF1 was the only independent prognostic factor for event free survival (RR 23.5; p=0.03). In fact, 6 of the 7 patients (86%) with an event had a deletion of IKZF1, of whom 2 had a deletion of the entire IKZF1 gene, and 4 patients had a focal deletion resulting in isoform 6. In conclusion, we found deletions in B-cell development genes in a comparable frequency as in high-risk types of ALL without DS. Especially a high incidence of IKAROS deletions was found, which identified an independent poor prognostic group within the DS ALL patients. The high frequency of IKZF1 deletions may in part be responsible for the worse prognosis of DS ALL compared to non-DS ALL as reported by some groups. Chromosomal location Number* Cytogenetics - Hyperdiploidy - 2/29 (6.9%) - BCR/ABL t(9;22) 1/26 (3.8%) - TEL/AML t(12;21) 2/34 (5.9%) JAK2 R683 mutation 9p24 5/34 (14.7%) B-cell development genes - IKZF1 7p12 14/34 (41.2%) - VPREB1 22q11.22 6/34 (17.6%) - PAX5 9p13.2 4/34 (11.7%) - EBF1 5q33.3 0 - TCF3 19p13.3 0 * Cytogenetic information was not always available for all patients Disclosures: No relevant conflicts of interest to declare.

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Volejnikova, Jana, Ester Mejstrikova, Karel Svojgr, Jan Stary, Jan Trka et Eva Fronkova. « Prognostic Impact of Ikaros (IKZF1) Gene Alterations In Childhood ALL Treated with ALL IC-BFM 2002 Protocol : A Comparison of Gene Expression and Genomic-Based Methods. » Blood 116, n^o 21 (19 novembre 2010) : 1656. http://dx.doi.org/10.1182/blood.v116.21.1656.1656.

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Abstract Abstract 1656 Introduction: Recently, Ikaros (IKZF1) gene alterations were found to predict poor prognosis in childhood acute lymphoblastic leukemia (ALL). Thus, the implementation of IKZF1 status into the risk group stratification is discussed. So far, limited data are available concerning both IKZF1 importance in different treatment protocols for Ph-negative ALL and the choice of the best diagnostic method. In this study, we compared two methods based on either genomic DNA examination or gene expression analysis, and their prognostic impact within a treatment protocol for childhood ALL. Methods: Gene expression of functional (IK1, IK2) and non-DNA binding (IK4, IK6, IK8) IKZF1 isoforms was semi-quantitatively evaluated using Lab-on-a-chip (Agilent) electrophoresis and reported either as an absolute level or relatively to the total isoform signal. The thresholds for abnormal gene expression were set based on the analysis of peripheral blood (PB) of healthy donors, remission bone marrow (BM) samples of children with ALL, and sorted B- and T-cell precursor subpopulations. MLPA (multiplex ligation-dependent probe amplification) reaction including probes for Ikaros exons 1 to 8 was performed on BM DNA samples and the products were analyzed with the Coffalyser v9.4 software. Results: Results of both gene expression and MLPA analysis in the BM were available for 120 of 193 children diagnosed with ALL between 2002 and 2005. MLPA analysis revealed a deletion of at least one exon of IKZF1 gene in 17/120 (14%) patients. Of note, two patients with this deletion underwent a lineage switch (LS) from ALL to AML during the induction treatment. The entire IKZF1 gene was mononoallelically deleted in 3 patients. The ratio between non-DNA binding (IK4, IK4del, IK4A, IK6, Ik6del, IK8) and functional (IK1 and IK2) isoform expression was significantly elevated (non-DNA binding isoforms>70%) in 21 of 120 (18%) patients. The expression of a dominant-negative IK6 isoform was significantly elevated (>20% of total) in 7 of 120 (6%) patients. Surprisingly, gene deletion on one allele was not accompanied by decrease of total IKZF1 gene expression. On the contrary, patients with IKZF1 deletion had higher total IKZF1 transcript level than those without deletion (p=0.008, Mann Whitney), but it was not possible to set any reliable expression threshold for the prediction of gene deletion. The change on a DNA level was not always reflected in relative gene expression: Of 17 patients with gene deletion, only 7 had significantly altered short/long isoform ratio and 5 patients had an increased expression of IK6. Conversely, of 7 patients with IK6 overexpression, two patients had no DNA alteration, suggesting a different mechanism of altered gene expression. We next evaluated the prognostic impact of IKZF1 alterations in 113 patients treated with ALL IC-BFM 2002 protocol (5 patients were excluded due to Ph-positive ALL with imatinib-based treatment and 2 patients due to treatment change after LS). Patients with IKZF1 gene deletion had significantly worse relapse-free survival (RFS) than other patients (5-year RFS 50.0±14.4% vs. 90.8±2.9%, p=0.0002). The presence of IKZF1 deletion did not correlate with minimal residual disease (MRD) during induction treatment (days 8, 15, 33), neither in BM nor in PB. Patients with IK6 overexpression had 5-year RFS 50.0±20.4% compared to 88.4± 3.2% in those with low IK6 expression (p=0.004). The elevated short/long isoform ratio (>70%) had no prognostic impact. The best prediction of relapse was achieved via combining two factors: the presence of IKZF1 deletion detected by MLPA or the relative IK6 overexpression (>50% of total isoform signal). The 5-year RFS was 50.0±13.4% for this group (14 pts, 7 relapses) compared to 91.6±2.8% for other patients (99 pts, 8 relapses, p<0.0001). Conclusion: This study confirmed that the presence of Ikaros gene alterations was connected with a high risk of relapse also in a BFM-based protocol for Ph-negative childhood ALL treatment. The deletion within IKZF1 locus did not necessarily correlate with an altered Ikaros gene expression. Ideally, both genomic and gene expression-based approach should be applied together for the evaluation of prognosis. However, if this is not possible, the examination of DNA changes by MLPA identifies more patients who subsequently relapse than the gene expression-based approach. Support: VZ MSM 0021620813, P301/10/1877, IGA NS/10472-3 Disclosures: No relevant conflicts of interest to declare.

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Zhang, Jinghui, Charles Mullighan, Richard Harvey, William L. Carroll, I.-Ming L. Chen, Meenakshi Devidas, Eric Larsen et al. « Lack of Somatic Sequence Mutations In Protein Tyrosine Kinase Genes Other Than the JAK Kinase Family In High Risk B-Precursor Childhood Acute Lymphoblastic Leukemia (ALL) : A Report From the Children's Oncology Group (COG) High-Risk (HR) ALL TARGET Project ». Blood 116, n^o 21 (19 novembre 2010) : 2752. http://dx.doi.org/10.1182/blood.v116.21.2752.2752.

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Abstract Abstract 2752 Introduction: We recently identified a poor prognostic subgroup of pediatric BCR-ABL1 negative ALL patients characterized by deletion of IKZF1 (encoding the lymphoid transcription factor IKAROS) and a gene expression signature similar to BCR-ABL1 positive ALL, raising the possibility of activated tyrosine kinase signaling within this leukemia subtype. Targeted sequencing revealed activating sequence mutations in the Janus tyrosine kinases (JAK1 (N=3), JAK2 (N=17) and JAK3 (N=1)) in 21 of 187 (11.2%) BCR-ABL1 negative, high-risk pediatric ALL cases. All 21 cases with JAK mutations had the BCR-ABL1-like expression profile, accounting for about 50% of the cases with this phenotype, suggesting that mutations in JAK kinases account for some, but not all, cases with this distinctive profile. To determine whether mutations in other kinases might also be associated with this distinctive gene expression profile, we sequenced 126 genes encoding tyrosine kinases and mediators of kinase signaling in an additional 46 high-risk ALL cases with a BCR-ABL1-like expression profile. The genes sequenced included the entire tyrosine kinome. Methods: The 46 leukemia specimens studied were from patients enrolled on COG clinical trials for high risk ALL (P9906, n=23 and AALL0232, n=23), with risk defined primarily by elevated WBC and/or age > 10 years. All 46 cases had a BCR-ABL1 like expression profile. The 23 P9906 cases all lacked JAK mutations, while 3 of the 23 AALL0232 cases were found to have activating JAK mutations (JAK1 (N=1), JAK2 (N=2)). The entire coding region and UTRs of each gene was amplified by PCR of whole genome amplified genomic DNA, and subjected to Sanger sequencing. A CEPH sample (NA19085) was also included as a normal control DNA. Results: A total of 1,149,117 bases were sequenced bi-directionally for each sample; 96% of the targeted bases were covered with high-quality sequencing data. We identified a total of 2,302 variations predicted to change protein sequences, 173 of which are novel, putative variations after removing germline variations found in dbSNP, The Cancer Genome Atlas Project (TCGA) and the normal CEPH sample NA19085 in this study. For each novel variation, the tumor DNA was resequenced and matching normal DNA was sequenced to validate the original observation and to distinguish somatic from inherited variants. The results show that 105 variations are germline, 20 are false positives while the remaining markers failed in validation assay. Aside from 1 FLT3 mutation (23aainsN609), there are no confirmed somatic mutations in any other tyrosine kinase genes. Conclusion: Aside from JAK mutations, somatically acquired sequence mutations in tyrosine kinase genes are rare in children with high risk ALL and BCR-ABL1 like gene expression profiles. We are pursuing the identification of alternative mechanisms for kinase activation that might explain the distinctive expression profile observed in these cases. Disclosures: Relling: St. Jude Children's Research Hospital: Employment, Patents & Royalties; Enzon Pharmaceuticals: Research Funding. Hunger:bristol myers squibb: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; eisai: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Swindlehurst, Cathy A., Leah Fung, Kyle W. H. Chan, Sabine Ottilie, Ashkan Shahbandi, Christopher L. Morris, Oliva L. Francis, Terrence Bennet, Shannalee R. Martinez et Kimberly J. Payne. « Two New Classes of Drugs to Target Chemotherapy Resistant and High Risk B-ALL ». Blood 118, n^o 21 (18 novembre 2011) : 2590. http://dx.doi.org/10.1182/blood.v118.21.2590.2590.

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Abstract Abstract 2590 Survival remains less than 50% for children and young adults with relapsing acute lymphoblastic leukemia (ALL). Increases in ALL survival over the last 50 years have been due largely to modifications in the use of existing therapies rather than the development of new drugs. B-cell ALL (B-ALL) is the most common childhood malignancy. New therapies are needed to target B-ALL that is resistant to conventional therapies and/or harbors driver molecular lesions (such as IKZF deletion or dysregulated CRLF2 expression) that have been linked with high-risk B-ALL. Here we evaluate the ability of two new classes of drugs to target B-ALL that is resistant to vincristine and/or doxorubicin, as well as B-ALL with IKZF or CRLF2 lesions. NovoMedix has recently developed two new classes of drugs with nanomolar efficacy in cell models of high-risk B-ALL (drug resistant Nalm-6, SupB15 [Ikaros deletion], and MHH-CALL-4 [CRLF-2d]) and demonstrated safety in animals. Both classes of drugs consist of novel drug-like molecules with molecular weights <400. IC50s for representatives of each class of drugs are shown in Table I. Note that the resistant cell lines are 650 times more resistant to vincristine and 15 times more resistant to doxorubicin with little to no change in efficacy for NM814 and NM869. This indicates that these drugs could be used in combination with current standard of care therapies as well as salvage therapy for relapsed, refractory disease. Standard combination therapy is associated with systemic toxicities that have long term consequences. New drugs that enhance standard multidrug combinations without overlapping toxicities would be of great benefit. Drugs described here have been tested in animals and are safe and effective in another cancer model, resulting in significant decrease in tumor volumes with no significant decrease in animal weights and no other signs of toxicity over the course of the 40 day study.Table 1IC50s for Drugs on High Risk B-ALLNalm-6Resistant Nalm-6SupB15MHH-CALL-4NM814 (furan)400 nM300 nM2 μM300 nMNM869 (tetrazole)50 nM100 nM400 nM200 nMVincristine0.2 nM130 nMn.dn.d.Doxorubicin20 nM300 nMn.d.n.d. Both NM814 and NM869 induce strong caspase activity at 16 hours that is inhibited by pan-3/7, 8, and 9 caspase inhibitors. This suggests that apoptosis is the major mechanism of cell death (confirmed by flow cytometry) and that a signaling cascade and/or multiple pathways are targeted by these drugs. Both drugs also inhibit cyclin D3 expression (assessed by Western blot) in Nalm-6 and SupB15 (and cyclin D1 in other cell lines), indicating that they induce cell cycle arrest. Furthermore, in a HeLa cell extract in vitro translation assay, both compounds inhibit protein translation, a major mechanism for regulation of cell cycle proteins, such as the cyclins. Additional mechanisms of action are divergent: B-ALL treated with NM869 continued to synthesize DNA but failed to undergo mitosis as indicated by the accumulation of hyperdiploid (4N) cells suggesting that it can act as a mitotic inhibitor; while NM814 strongly upregulated several tumor suppressor genes, including p21 and histone H2A.x in B-ALL cell lines. Ongoing studies are evaluating efficacy in high-risk primary B-ALL models. Data presented here establish these two classes of drugs as strong candidates for combination therapies to target high-risk and relapsing B-ALL with the potential for less toxic multi-drug combinations. Disclosures: Swindlehurst: Novomedix, LLC: Employment, Equity Ownership. Fung:Novomedix, LLC: Employment, Equity Ownership. Chan:Novomedix, LLC: Consultancy, Equity Ownership. Ottilie:Novomedix, LLC: Employment.

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Rawoof, Abdul, Guruprasadh Swaminathan, Shrish Tiwari, Rekha A. Nair et Lekha Dinesh Kumar. « LeukmiR : a database for miRNAs and their targets in acute lymphoblastic leukemia ». Database 2020 (1 janvier 2020). http://dx.doi.org/10.1093/database/baz151.

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Abstract Acute lymphoblastic leukemia (ALL) is one of the most common hematological malignancies in children. Recent studies suggest the involvement of multiple microRNAs in the tumorigenesis of various leukemias. However, until now, no comprehensive database exists for miRNAs and their cognate target genes involved specifically in ALL. Therefore, we developed ‘LeukmiR’ a dynamic database comprising in silico predicted microRNAs, and experimentally validated miRNAs along with the target genes they regulate in mouse and human. LeukmiR is a user-friendly platform with search strings for ALL-associated microRNAs, their sequences, description of target genes, their location on the chromosomes and the corresponding deregulated signaling pathways. For the user query, different search modules exist where either quick search can be carried out using any fuzzy term or by providing exact terms in specific modules. All entries for both human and mouse genomes can be retrieved through multiple options such as miRNA ID, their accession number, sequence, target genes, Ensemble-ID or Entrez-ID. User can also access miRNA: mRNA interaction networks in different signaling pathways, the genomic location of the targeted regions such as 3′UTR, 5′UTR and exons with their gene ontology and disease ontology information in both human and mouse systems. Herein, we also report 51 novel microRNAs which are not described earlier for ALL. Thus, LeukmiR database will be a valuable source of information for researchers to understand and investigate miRNAs and their targets with diagnostic and therapeutic potential in ALL. Database URL: http://tdb.ccmb.res.in/LeukmiR/

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Almeida, Renata Santos, Thailany Thays Gomes, Felipe Souza Araújo, Sávio Augusto Vieira de Oliveira, Jair Figueredo Santos, Eduardo Antônio Donadi et Norma Lucena-Silva. « Differentially Expressed Bone Marrow microRNAs Are Associated With Soluble HLA-G Bone Marrow Levels in Childhood Leukemia ». Frontiers in Genetics 13 (14 juin 2022). http://dx.doi.org/10.3389/fgene.2022.871972.

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HLA-G is a nonclassical histocompatibility class I molecule that plays a role in immune vigilance in cancer and infectious diseases. We previously reported that highly soluble HLA-G (sHLA-G) levels in the bone marrow were associated with a high blood cell count in T-acute lymphoblastic leukemia, a marker associated with a poor prognosis. To understand the posttranscriptional HLA-G gene regulation in leukemia, we evaluated the bone marrow microRNA profile associated with the HLA-G bone marrow mRNA expression and sHLA-G bone marrow levels in children exhibiting acute leukemia (B-ALL, T-ALL, and AML) using massively parallel sequencing. Ten differentially expressed miRNAs were associated with high sHLA-G bone marrow levels, and four of them (hsa-miR-4516, hsa-miR-486-5p, hsa-miR-4488, and hsa-miR-5096) targeted HLA-G, acting at distinct HLA-G gene segments. For qPCR validation, these miRNA expression levels (ΔCt) were correlated with HLA-G5 and RREB1 mRNA expressions and sHLA-G bone marrow levels according to the leukemia subtype. The hsa-miR-4488 and hsa-miR-5096 expression levels were lower in B-ALL than in AML, while that of hsa-miR-486-5p was lower in T-ALL than in AML. In T-ALL, hsa-miR-5096 correlated positively with HLA-G5 and negatively with sHLA-G. In addition, hsa-miR-4516 correlated negatively with sHLA-G levels. In AML, hsa-miR-4516 and hsa-miR-4488 correlated positively with HLA-G5 mRNA, but the HLA-G5 negatively correlated with sHLA-G. Our findings highlight the need to validate the findings of massively parallel sequencing since the experiment generally uses few individuals, and the same type of leukemia can be molecularly quite variable. We showed that miRNA’s milieu in leukemia’s bone marrow environment varies according to the type of leukemia and that the regulation of sHLA-G expression exerted by the same miRNA may act by a distinct mechanism in different types of leukemia.

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