Journal articles on the topic 'Chronic myeloid leukemia gene therapy'
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1
Ghosn, Youssef, Mohammed Hussein Kamareddine, Antonios Tawk, Carlos Elia, Ahmad El Mahmoud, Khodor Terro, Nadia El Harake, Bachar El-Baba, Joseph Makdessi, and Said Farhat. "Inorganic Nanoparticles as Drug Delivery Systems and Their Potential Role in the Treatment of Chronic Myelogenous Leukaemia." Technology in Cancer Research & Treatment 18 (January 1, 2019): 153303381985324. http://dx.doi.org/10.1177/1533033819853241.
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Chronic myeloid leukemia is a myeloproliferative disease where cells of myeloid linage display a t(9;22) chromosomal translocation leading to the formation of the BCR/ABL fusion gene and the continuous activation of tyrosine kinases. This malignancy has a peak incidence at 45 to 85 years, accounting for 15% of all leukemias in adults. Controlling the activity of tyrosine kinase became the main strategy in chronic myeloid leukemia treatment, with imatinib being placed at the forefront of current treatment protocols. New approaches in future anticancer therapy are emerging with nanomedicine being gradually implemented. Setting through a thorough survey of published literature, this review discusses the use of inorganic nanoparticles in chronic myeloid leukemia therapy. After an introduction on the basics of chronic myeloid leukemia, a description of the current treatment modalities of chronic myeloid leukemia and drug-resistance mechanisms is presented. This is followed by a general view on the applications of nanostrategies in medicine and then a detailed breakdown of inorganic nanocarriers and their uses in chronic myeloid leukemia treatment.
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Jamieson, Catriona H. "Chronic Myeloid Leukemia Stem Cells." Hematology 2008, no. 1 (January 1, 2008): 436–42. http://dx.doi.org/10.1182/asheducation-2008.1.436.
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Abstract Chronic myeloid leukemia (CML) is typified by robust marrow and extramedullary myeloid cell production. In the absence of therapy or sometimes despite it, CML has a propensity to progress from a relatively well tolerated chronic phase to an almost uniformly fatal blast crisis phase. The discovery of the Philadelphia chromosome followed by identification of its BCR-ABL fusion gene product and the resultant constitutively active P210 BCR-ABL tyrosine kinase, prompted the unraveling of the molecular pathogenesis of CML. Ground-breaking research demonstrating that BCR-ABL was necessary and sufficient to initiate chronic phase CML provided the rationale for targeted therapy. However, regardless of greatly reduced mortality rates with BCR-ABL targeted therapy, most patients harbor quiescent CML stem cells that may be a reservoir for disease progression to blast crisis. While the hematopoietic stem cell (HSC) origin of CML was first suggested over 30 years ago, only recently have the HSC and progenitor cell–specific effects of the molecular mutations that drive CML been investigated. This has provided the impetus for investigating the genetic and epigenetic events governing HSC and progenitor cell resistance to therapy and their role in disease progression. Accumulating evidence suggests that the acquired BCR-ABL mutation initiates chronic phase CML and results in aberrant stem cell differentiation and survival. This eventually leads to the production of an expanded progenitor population that aberrantly acquires self-renewal capacity resulting in leukemia stem cell (LSC) generation and blast crisis transformation. Therapeutic recalcitrance of blast crisis CML provides the rationale for targeting the molecular pathways that drive aberrant progenitor differentiation, survival and self-renewal earlier in disease before LSC predominate.
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Deininger, Michael W. "Diagnosing and Managing Advanced Chronic Myeloid Leukemia." American Society of Clinical Oncology Educational Book, no. 35 (May 2015): e381-e388. http://dx.doi.org/10.14694/edbook_am.2015.35.e381.
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Clinical staging of chronic myeloid leukemia (CML) distinguishes between chronic phase (CP-CML), accelerated phase (AP-CML), and blastic phase (BP-CML), reflecting its natural history in the absence of effective therapy. Morphologically, transformation from CP-CML to AP/BP-CML is characterized by a progressive or sudden loss of differentiation. Multiple different somatic mutations have been implicated in transformation from CP-CML to AP/BC-CML, but no characteristic mutation or combination of mutations have emerged. Gene expression profiles of AP-CML and BP-CML are similar, consistent with biphasic evolution at the molecular level. Gene expression of tyrosine kinase inhibitor (TKI)–resistant CP-CML and second CP-CML resemble AP/BP-CML, suggesting that morphology alone is a poor predictor of biologic behavior. At the clinical level, progression to AP/BP-CML or resistance to first-line TKI therapy distinguishes a good risk condition with survival close to the general population from a disease likely to reduce survival. Progression while receiving TKI therapy is frequently caused by mutations in the target kinase BCR-ABL1, but progression may occur in the absence of explanatory BCR-ABL1 mutations, suggesting involvement of alternative pathways. Identifying patients in whom milestones of TKI response fail to occur or whose disease progress while receiving therapy requires appropriate molecular monitoring. Selection of salvage TKI depends on prior TKI history, comorbidities, and BCR-ABL1 mutation status. Despite the introduction of novel TKIs, therapy of AP/BP-CML remains challenging and requires accepting modalities with substantial toxicity, such as hematopoietic stem cell transplantation (HSCT).
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Trela, Ewelina, Sylwester Glowacki, and Janusz Błasiak. "Therapy of Chronic Myeloid Leukemia: Twilight of the Imatinib Era?" ISRN Oncology 2014 (January 30, 2014): 1–9. http://dx.doi.org/10.1155/2014/596483.
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Chronic myeloid leukemia (CML) results from the clonal expansion of pluripotent hematopoietic stem cells containing the active BCR/ABL fusion gene produced by a reciprocal translocation of the ABL1 gene to the BCR gene. The BCR/ABL protein displays a constitutive tyrosine kinase activity and confers on leukemic cells growth and proliferation advantage and resistance to apoptosis. Introduction of imatinib (IM) and other tyrosine kinase inhibitors (TKIs) has radically improved the outcome of patients with CML and some other diseases with BCR/ABL expression. However, a fraction of CML patients presents with resistance to this drug. Regardless of clinical profits of IM, there are several drawbacks associated with its use, including lack of eradication of the malignant clone and increasing relapse rate resulting from long-term therapy, resistance, and intolerance. Second and third generations of TKIs have been developed to break IM resistance. Clinical studies revealed that the introduction of second-generation TKIs has improved the overall survival of CML patients; however, some with specific mutations such as T315I remain resistant. Second-generation TKIs may completely replace imatinib in perspective CML therapy, and addition of third-generation inhibitors may overcome resistance induced by every form of point mutations.
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Warfvinge, Rebecca, Mikael Sommarin, Parashar Dhapola, Ulrich Pfisterer, Linda Geironson Ulfsson, Fatemeh Safi, Ram Krishna Thakur, Johan Richter, and Göran Karlsson. "Characterization of Leukemic Stem Cells Heterogeneity in Chronic Myeloid Leukemia." Blood 134, Supplement_1 (November 13, 2019): 4140. http://dx.doi.org/10.1182/blood-2019-130956.
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In chronic myeloid leukemia (CML), a rare subset of leukemic stem cells (LSC) persists in patients responding to conventional tyrosine kinase inhibitor (TKI) therapy. The failure to eradicate these LSCs results in indefinite therapy dependence and a risk of leukemic relapse. However, the conventional LSC compartment (Lin-CD34+CD38-) is highly heterogeneous where only a subpopulation is believed to be functional, TKI-insensitive LSCs. Previously, using single-cell gene expression analysis we characterized the heterogeneity within the LSC population (Lin-CD34+CD38-) in CML patients using a selected panel of 96 primers. Interestingly, by comparing LSC heterogeneity at diagnosis with the heterogeneity following 3 months of TKI therapy we uncovered a therapy-insensitive, quiescent subpopulation, which could be isolated at high-purity using a combination of the surface markers: Lin-CD34+CD38-CD45RA-cKIT-CD26+ (Warfvinge, Geironson, Sommarin et al., 2017). Here, we expand the single-cell analysis of CML LSC populations to include combined immunophenotype-/RNA sequencing analysis (CITE-seq). CITE-seq allows for unbiased, further in-depth transcriptome analysis as wells as immunophenotypic characterization by pre-staining cells with a panel of DNA-barcoded antibodies prior to sequencing. DNA-barcoded antibodies convert the protein expression into readable sequences through unique oligo-conjugates as identifiers. Using CITE-seq with a panel of 44 distinct surface markers designed to immunophenotypically differentiate between stem/progenitors cells and leukemic clones we simultaneously characterize the molecular and immunophenotypic heterogeneity within Lin-CD34+/Lin-CD34+CD38- CML stem/progenitor compartment at diagnosis. Additionally by comparing the LSCs transcriptome from patients with different therapeutic outcome after 12 months of therapy we describe how differences in heterogeneity and the presence of immunophenotypic therapy-insensitive LSCs at diagnosis (Lin-CD34+CD38-CD45RA-cKIT-CD26+) contribute to therapy response. Disclosures Richter: Novartis: Consultancy; Pfizer: Consultancy, Research Funding.
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Husnain, Muhammad, Trent Wang, Maikel Valdes, James Hoffman, and Lazaros Lekakis. "Multiple Myeloma in a Patient with ANKRD26-Related Thrombocytopenia Successfully Treated with Combination Therapy and Autologous Stem Cell Transplant." Case Reports in Hematology 2019 (June 2, 2019): 1–3. http://dx.doi.org/10.1155/2019/9357572.
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Ankyrin repeat domain-containing protein 26- (ANKRD26-) related thrombocytopenia is a rare, autosomal dominant condition caused by ANKRD26 gene mutation. ANKRD26-related thrombocytopenia is characterized by moderate thrombocytopenia with minimal bleeding, normal platelet size, and dysmegakaryopoiesis on bone marrow evaluation. ANKRD26 mutation has been previously associated with myeloid malignancies, including acute myeloid leukemia, myelodysplastic syndrome, and chronic myeloid leukemia. We report the first case of multiple myeloma in a patient with ANKRD26 related thrombocytopenia. The patient was successfully treated with contemporary combination therapy followed by melphalan-conditioned autologous stem cell transplant for his multiple myeloma despite preexisting thrombocytopenia.
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Gao, Liquan, Ilaria Bellantuono, Annika Elsässer, Stephen B. Marley, Myrtle Y. Gordon, John M. Goldman, and Hans J. Stauss. "Selective elimination of leukemic CD34+ progenitor cells by cytotoxic T lymphocytes specific for WT1." Blood 95, no. 7 (April 1, 2000): 2198–203. http://dx.doi.org/10.1182/blood.v95.7.2198.
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Abstract Hematologic malignancies such as acute and chronic myeloid leukemia are characterized by the malignant transformation of immature CD34+ progenitor cells. Transformation is associated with elevated expression of the Wilm's tumor gene encoded transcription factor (WT1). Here we demonstrate that WT1 can serve as a target for cytotoxic T lymphocytes (CTL) with exquisite specificity for leukemic progenitor cells. HLA-A0201– restricted CTL specific for WT1 kill leukemia cell lines and inhibit colony formation by transformed CD34+ progenitor cells isolated from patients with chronic myeloid leukemia (CML), whereas colony formation by normal CD34+ progenitor cells is unaffected. Thus, the tissue-specific transcription factor WT1 is an ideal target for CTL-mediated purging of leukemic progenitor cells in vitro and for antigen-specific therapy of leukemia and other WT1-expressing malignancies in vivo.
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Gao, Liquan, Ilaria Bellantuono, Annika Elsässer, Stephen B. Marley, Myrtle Y. Gordon, John M. Goldman, and Hans J. Stauss. "Selective elimination of leukemic CD34+ progenitor cells by cytotoxic T lymphocytes specific for WT1." Blood 95, no. 7 (April 1, 2000): 2198–203. http://dx.doi.org/10.1182/blood.v95.7.2198.007k38_2198_2203.
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Hematologic malignancies such as acute and chronic myeloid leukemia are characterized by the malignant transformation of immature CD34+ progenitor cells. Transformation is associated with elevated expression of the Wilm's tumor gene encoded transcription factor (WT1). Here we demonstrate that WT1 can serve as a target for cytotoxic T lymphocytes (CTL) with exquisite specificity for leukemic progenitor cells. HLA-A0201– restricted CTL specific for WT1 kill leukemia cell lines and inhibit colony formation by transformed CD34+ progenitor cells isolated from patients with chronic myeloid leukemia (CML), whereas colony formation by normal CD34+ progenitor cells is unaffected. Thus, the tissue-specific transcription factor WT1 is an ideal target for CTL-mediated purging of leukemic progenitor cells in vitro and for antigen-specific therapy of leukemia and other WT1-expressing malignancies in vivo.
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Xin, Jiajia, Dandan Yin, Wei Fu, Hui-Jie Zhang, Yaozhen Chen, Yazhou Wang, Mingkai Li, and Xingbin Hu. "A Novel Compound Inhibits Chronic Myeloid Leukemia Via Upregulating Apoptosis." Blood 126, no. 23 (December 3, 2015): 5559. http://dx.doi.org/10.1182/blood.v126.23.5559.5559.
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Abstract Chronic myeloid leukemia (CML) is a myeloid proliferative disorder mainly result from chimeric protein BCR-ABL1 encoded by a fusion gene at the t(9;22) (q34;q11) chromosomal translocation. Intrinsically, this recombined protein results in an increased tyrosine kinase (TK) activity that directly related to hematopoietic stem cell malignant proliferation. Consequently, the drugs derived from tyrosine kinase inhibitors (TKI) have been developed as an infective therapy, and greatly improved patients survival in clinic. Unfortunately, single TKI administration led to toxicities or tolerance in long-term treated CML patients. Even worse is, about 5% CML patients were not caused by bcr-abl gene mutation. Thus better medicines are badly needed to compensate CML therapy. Herein, we investigated the undefined function of a biscoumarins. The new synthesized compound exhibited a null toxicity on HUVECs but intensive toxicity on K562 leukemic cells. Subsequent results demonstrated that it efficiently inhibited the expansion of human CML cell line and bone marrow cells of SCL-tTA-BCL/ABL transgenic model mice via increased apoptosis. Critically, we also showed that CD34+ bone marrow leukemic cells collected from patients underwent more apoptosis after treated by the biscoumarins derivate. To extend these results into vivo, we observed a prolonged survival of bcr-abl transgenic mice treated by derivate mono-therapy or combination with imatinib compared to those of untreated or imatinib-treated CML mice. All together, these results indicated that this biscoumarins derivate may have novel potential as a therapeutic agent against CML. Disclosures No relevant conflicts of interest to declare.
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Deshmukh, Komal Galani, and Katalin Kelemen. "Lessons Learned from Donor Cell-Derived Myeloid Neoplasms: Report of Three Cases and Review of the Literature." Life 12, no. 4 (April 8, 2022): 559. http://dx.doi.org/10.3390/life12040559.
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Donor-cell derived myeloid neoplasm (DDMN), a rare complication after allogeneic hematopoietic cell transplantation (HCT), is of interest for its potential to reveal donor-derived and host-derived factors that contribute to the pathogenesis of leukemia. The accurate diagnosis of donor-derived leukemias has been facilitated by the more frequent use of molecular techniques. In this study, we describe three additional cases of DDMN; the first reported case of donor-derived chronic myelomonocytic leukemia (CMML), one acute myeloid leukemia (AML) with t(8;21)(q22;22); RUNX1-RUNX1T1 and one donor-derived MDS with deletion 5q. A review of the cytogenetic profiles of previously reported DDMN indicates a significant contribution of therapy-related myeloid neoplasms. Cases with direct evidence of donor- or recipient-dependent factors are rare; a role of direct transfer of leukemic cells, genomic instability of the donor, abnormal gene methylation in donor cells, proleukemic potential of abnormal stromal niche, and the role of immunological surveillance after transplantation has been observed. The role of additional potential pathogenetic factors that are without clinically observed evidence are also reviewed.
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Shiba, Norio, Tomohiko Taki, Myoung-ja Park, Masayuki Nagasawa, Jyunko Takita, Motohiro Kato, Takashi Kanazawa, Manabu Sotomatsu, Hirokazu Arakawa, and Yasuhide Hayashi. "CBL Mutations In Therapy-Related Leukemia and Infant Leukemia." Blood 116, no. 21 (November 19, 2010): 2149. http://dx.doi.org/10.1182/blood.v116.21.2149.2149.
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Abstract Abstract 2149 Recent reports of somatic mutations of the CBL proto-oncogene in myeloid neoplasms are intriguing, because these CBL mutations were shown to results in aberrant tyrosine kinase signaling, which would lead also to activation of RAS signaling pathways. We and others reported that CBL mutations occurred in a variety of myeloid neoplasms, including de novo acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and MDS/myeloproliferative neoplasm, especially in chronic myelomonocytic leukemia (CMML) and juvenile myelomonocytic leukemia (JMML). The importance of CBL mutations concerning leukemogenesis is substantially increased. We investigated CBL mutations in 20 therapy-related leukemia/MDS (t-Leuk/MDS) cases and 26 infant leukemia cases. Homozygous mutation of theCBL gene (P417R), which was located in the RING finger domain, was identified in one out of 20 (5%) t-Leuk/MDS cases. This patient was a 5 year-old boy, whose biopsied specimen of the buccal lymph node showed malignant lymphoma (diffuse large T cell type, MT1(+), MB1(-), UCHL1(+)). No pathogenic nucleotide changes were identified in the CBL gene in the initial sample. Subsequently, the patient was treated with chemotherapy including VP-16 (200 mg/m2) given twice weekly. Nineteen months after initial diagnosis, he was diagnosed as having therapy-related leukemia with t(5;21) and MLL gene rearrangement due to VP-16. Furthermore, CBL gene mutations were found in 3 of 26 (12%) infant leukemia cases with 11q23 translocation/MLL gene rearrangement. CBL gene mutations were located in splice site in intron 8 and the RING finger domain (Y371H, in 2 cases), SNP array analysis (Affymetrix, GeneChip) of these cases with mutated CBL gene disclosed 11q-acquired uniparental disomy in all cases, but not in cases with wild-type CBL. CBL mutation has not been reported in acute leukemia with 11q23 translocation/MLL gene rearrangement. To our knowledge, these are the first t-Leuk/MDS case and infant cases with 11q23 translocation/MLL rearrangement, suggesting that CBL is mutated in a unique subset of t-Leuk/MDS and infant leukemia which is considered to play a pathogenic role in the development of t-Leuk/MDS and infant leukemia. Further accumulation of cases with t-Leuk/MDS and infant leukemia having the CBL mutation is needed. Disclosures: No relevant conflicts of interest to declare.
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Giona, Fiorina, and Simona Bianchi. "Update in Childhood Chronic Myeloid Leukemia." Hemato 3, no. 4 (November 5, 2022): 718–31. http://dx.doi.org/10.3390/hemato3040048.
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Chronic myeloid leukemia (CML) in childhood represents only 3% of newly diagnosed pediatric leukemia. The diagnostic hallmark of CML is the Philadelphia (Ph) chromosome, which derives from the fusion of the ABL1-oncogene located on chromosome 9 to the breakpoint cluster region (BCR) gene on chromosome 22, resulting in a constitutively dysregulated ABL1 tyrosine kinase, either as 210 kDa or 190 kDa. Depending on the localization of the breakpoint site within the major BCR region, the majority of CML patients exhibit transcripts with either the b3a2 or b2a2 junction, or both. Several questions are still open with regard to childhood CML, especially concerning the biologic and clinical features of the disease, and the treatment of choice for pediatric patients with CML. Moreover, over the last few years, several tyrosine kinase inhibitors (TKIs) have been available for children and adolescents with CML, and current clinical practice investigates what the effective and optimal doses of TKIs are in these two categories of patients. The use of TKIs in pediatric patients with CML has also opened up questions on the following items: (1) the long-term effects of these drugs on children; (2) the management of pediatric CML forms resistant or intolerant to TKIs; (3) the monitoring of disease outcomes during treatment; (4) and the right timing to discontinue therapy. Despite the efficacy of TKIs also in the pediatric population, the potential late adverse effects, and the drug resistance, leave open the possibility of allogeneic hematopoietic stem cell transplantation as a treatment option in pediatric CML. Published data and personal experiences regarding these issues will be analyzed and discussed.
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Liu, Yang, Gui Zhao, Cong-Fei Xu, Ying-Li Luo, Zi-Dong Lu, and Jun Wang. "Systemic delivery of CRISPR/Cas9 with PEG-PLGA nanoparticles for chronic myeloid leukemia targeted therapy." Biomaterials Science 6, no. 6 (2018): 1592–603. http://dx.doi.org/10.1039/c8bm00263k.
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Rudich, Alexander, Ramiro Garzon, and Adrienne Dorrance. "Non-Coding RNAs Are Implicit in Chronic Myeloid Leukemia Therapy Resistance." International Journal of Molecular Sciences 23, no. 20 (October 14, 2022): 12271. http://dx.doi.org/10.3390/ijms232012271.
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Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm initiated by the presence of the fusion gene BCR::ABL1. The development of tyrosine kinase inhibitors (TKIs) highly specific to p210BCR-ABL1, the constitutively active tyrosine kinase encoded by BCR::ABL1, has greatly improved the prognosis for CML patients. Now, the survival rate of CML nearly parallels that of age matched controls. However, therapy resistance remains a persistent problem in the pursuit of a cure. TKI resistance can be attributed to both BCR::ABL1 dependent and independent mechanisms. Recently, the role of non-coding RNAs (ncRNAs) has been increasingly explored due to their frequent dysregulation in a variety of malignancies. Specifically, microRNAs (miRNAs), circular RNAs (circRNAs), and long non-coding RNAs (lncRNAs) have been shown to contribute to the development and progression of therapy resistance in CML. Since each ncRNA exhibits multiple functions and is capable of controlling gene expression, they exert their effect on CML resistance through a diverse set of mechanisms and pathways. In most cases ncRNAs with tumor suppressing functions are silenced in CML, while those with oncogenic properties are overexpressed. Here, we discuss the relevance of many aberrantly expressed ncRNAs and their effect on therapy resistance in CML.
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Nam, Myung-Hyun, Ju-Yeon Kim, Soo-Young Yoon, Chae Seung Lim, Chang Kyu Lee, Yunjung Cho, Young-Kee Kim, and Kap No Lee. "JAK2 V617F Mutation In Atypical Chronic Myeloid Leukemia." Blood 116, no. 21 (November 19, 2010): 5069. http://dx.doi.org/10.1182/blood.v116.21.5069.5069.
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Abstract Abstract 5069 Atypical chronic myeloid leukemia (aCML) is a rare leukemic disorder which shows myelodysplastic and myeloproliferative features simultaneously. Some cases of JAK2 V617F mutation in aCML were reported before WHO criteria introduced (Jelinek J et al. Blood 2005; Jones AV et al. Blood 2005; Levine RL et al. Blood 2005). However, Fend F et al observed no JAK2 V617F mutation in aCML as defined by WHO classification (Fend F et al. Leuk Res 2008), which result was refuted by a case report (Campiotti L et al. Leuk Res 2009). Here we analyzed JAK2 V617F mutation with amplification refractory mutation system (ARMS) and direct sequencing in three cases of aCML and found a case with JAK2 V617F mutation. All three cases were diagnosed as aCML according to WHO classification and showed significant myelodysplastic/myeloproliferative features in peripheral blood and bone marrow aspirates. Absence of BCR/ABL1 gene rearrangement was confirmed by FISH analysis, and conventional cytogenetic analysis revealed trisomy 8 in a case with no JAK2 V617F mutation. The patient with JAK2 V617F mutation poorly responds with hydroxyurea therapy and is showing prolonged leukocytosis. Disclosures: No relevant conflicts of interest to declare.
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Byun, Hyang-Min, Shahrooz Eshaghian, Jia Yi Jiang, Si Ho Choi, John Soussa, Laleh Ramezani, Dan Douer, and Allen S. Yang. "DNA Methylation Analysis of 807 Genes in Chronic Myeloid Leukemia and Acute Promyelocytic Leukemia." Blood 110, no. 11 (November 16, 2007): 2122. http://dx.doi.org/10.1182/blood.v110.11.2122.2122.
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Abstract DNA methylation changes are a common finding in leukemia, and hypermethylation of CpG island promoters is associated with aberrant gene silencing. Some abnormal cancer related methylation changes have been associated with clinical phenotype including pathologic features, prognosis, and treatment response. However, other DNA methylation changes do not appear to have phenotypic consequences and may reflect a stochastic event or a downstream event of tumorogenesis, such as the CpG island methylator phenotype (CIMP). In order to obtain a better understanding of the DNA methylation changes found in leukemia we analyzed 18 acute promyelocytic leukemia (APL) and 36 chronic myeloid leukemia (CML) patients. We specifically chose to study APL and CML as these leukemia are initiated by specific genetic translocation events, t(15:17) and t(9:22) respectively. To measure the DNA methylation status, we used the GoldenGate Assay for Methylation and BeadArray technology from Illumina, Inc. The Standard Methylation Cancer Panel I from Illumina interrogates 1505 CpG sites, selected from 807 genes (231 genes contain one CpG site per gene, 463 genes contain two CpG sites and 114 genes have three or more CpG sites). In our study we found 142 and 269 genes that were hypermethylated in CML and APL. 31 genes were uniquely hypermethylated in CML, 158 genes were hypermethylated only in APL, and 111 genes were hypermethylated in both leukemias. There was a unique pattern of hypermethylated genes in each cancer; such there was a high concordance of hypermethylated genes within each leukemia type. These data suggest that the epigenetic events were a result of the genetic translocation BCR/ABL or PML/RARα (associated with chromosomal aberrations t(9:22) or t(15:17)) that initiates these leukemias. Analysis of the number of hypermethylated genes in these two leukemias showed a bimodal distribution suggestive of CIMP, however, closer examination showed that this bimodal distribution could be attributed to the two different types of leukemia. APL patients had mean of 280 genes hypermethylated while CML patients only had a mean of 193 genes hypermethylated. APL had a stronger methylator phenotype than CML for the loci studied, which underscores the possible relationship of CIMP to a genetic phenotype. Subset analysis of our CML samples by chronic phase (23 patients), accelerated phase (5 patients), and blast crisis (8 patients) revealed 42 genes that became hypermethylated with progression of CML. It is possible that hypermethylation of these genes are clinically important in the leukemia phenotype, and maybe targets for epigenetic therapy. We examined the DNA methylation changes induced by the DNA methylation inhibitor, azacitidine, in a patient with blast crisis CML and refractory to imatinib mesylate therapy. Azacitidine could reverse the aberrant hypermethylation associated with progression of CML to blast crisis and supports the use of this drug as an epigenetic therapy. Our data show that the majority of DNA hypermethylation events in leukemia are dependent on genetic events, but there is a subset of DNA hypermethylation events that are involved in the progression of leukemia and may be therapeutically reversed by DNA methylation inhibitors.
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Hodeib, Hossam, Dina Abd EL Hai, Mohamed A. Tawfik, Alzahraa A. Allam, Ahmed F. Selim, Mohamed E. Sarhan, Amal Selim, Nesreen M. Sabry, Wael Mansour, and Amira Youssef. "The Impact of SKP2 Gene Expression in Chronic Myeloid Leukemia." Genes 13, no. 6 (May 26, 2022): 948. http://dx.doi.org/10.3390/genes13060948.
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Introduction: The prognosis of chronic myeloid leukemia (CML) patients has been dramatically improved with the introduction of imatinib (IM), the first tyrosine kinase inhibitor (TKI). TKI resistance is a serious problem in IM-based therapy. The human S-phase kinase-associated protein 2 (SKP2) gene may play an essential role in the genesis and progression of CML. Aim of the study: We try to explore the diagnostic/prognostic impact of SKP2 gene expression to predict treatment response in first-line IM-treated CML patients at an early response stage. Patients and methods: The gene expression and protein levels of SKP2 were determined using quantitative RT-PCR and ELISA in 100 newly diagnosed CML patients and 100 healthy subjects. Results: SKP2 gene expression and SKP2 protein levels were significantly upregulated in CML patients compared to the control group. The receiver operating characteristic (ROC) analysis for the SKP2 gene expression level, which that differentiated the CML patients from the healthy subjects, yielded a sensitivity of 86.0% and a specificity of 82.0%, with an area under the curve (AUC) of 0.958 (p < 0.001). The ROC analysis for the SKP2 gene expression level, which differentiated optimally from the warning/failure responses, yielded a sensitivity of 70.59% and a specificity of 71.21%, with an AUC of 0.815 (p < 0.001). Conclusion: The SKP2 gene could be an additional diagnostic and an independent prognostic marker for predicting treatment responses in first-line IM-treated CML patients at an early time point (3 months).
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Soverini, Simona, Sara De Santis, Cecilia Monaldi, Samantha Bruno, and Manuela Mancini. "Targeting Leukemic Stem Cells in Chronic Myeloid Leukemia: Is It Worth the Effort?" International Journal of Molecular Sciences 22, no. 13 (June 30, 2021): 7093. http://dx.doi.org/10.3390/ijms22137093.
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Chronic myeloid leukemia (CML) is a classical example of stem cell cancer since it arises in a multipotent hematopoietic stem cell upon the acquisition of the t(9;22) chromosomal translocation, that converts it into a leukemic stem cell (LSC). The resulting BCR-ABL1 fusion gene encodes a deregulated tyrosine kinase that is recognized as the disease driver. Therapy with tyrosine kinase inhibitors (TKIs) eliminates progenitor and more differentiated cells but fails to eradicate quiescent LSCs. Thus, although many patients obtain excellent responses and a proportion of them can even attempt treatment discontinuation (treatment free remission [TFR]) after some years of therapy, LSCs persist, and represent a potentially dangerous reservoir feeding relapse and hampering TFR. Over the past two decades, intensive efforts have been devoted to the characterization of CML LSCs and to the dissection of the cell-intrinsic and -extrinsic mechanisms sustaining their persistence, in an attempt to find druggable targets enabling LSC eradication. Here we provide an overview and an update on these mechanisms, focusing in particular on the most recent acquisitions. Moreover, we provide a critical appraisal of the clinical relevance and feasibility of LSC targeting in CML.
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Shuvaev, Vasily, Karina Krutikova, Svetlana Menshakova, Natalya Kalinova, Irina Martynkevich, Lyubov Polushkina, Elena Belyakova, Yury Krivolapov, and Sergei Voloshin. "Atypical Chronic Myeloid Leukemia Challenge in Russian Hematology Practice." Blood 132, Supplement 1 (November 29, 2018): 5483. http://dx.doi.org/10.1182/blood-2018-99-114885.
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Abstract Background. The Atypical Chronic Myeloid Leukemia (aCML) and Chronic Neutrophilic Leukemia (CNL) had put in separate sections of myeloid neoplasms classification but have common entity and bone marrow changes. aCML and CNL hard to differentiate from each other. The main differential criterion is the proportion of immature white blood cells in blood, but it is not strong due to its instability. The achievement of recent years is discovering of aCML and CNL molecular factors: mutations in SETBP1 and CSFR3R genes gave the basis for the diagnosis confirmation in part of patients but could not differentiate between two nosologies. In addition, the access to the "uncommon" molecular diagnostic is complicated in routine clinical practice. Aim. At the abstract we would like to report the first, as we known, diagnosis of aCNL in Russia, that had been confirmed by molecular markers and is treating with target therapy. Materials and methods. The patient, female 51-year old has presented severe fatigue, pain, weight loss and burden under the left costal margin since Sep-2017. Results. The initial assessment has revealed massive splenomegaly (200x130x248 mm) with high WBC (133.9x109/L with left shift: blasts 1%, promyelocytes 6%, myelocytes 14%, metamylocytes 16%, bands 14%, segments 45%, lymphocytes 2%, monocytes 0%), mild anemia (10.4 g/dL) and normal platelets (223x109/L). There was neutrophil hyperplasia without eosinophilia and basophilia in myelogram. Initial diagnosis of typical CML was made but cytogenetic was normal and BCR-ABL (p190, p210) was negative. Atypical CML was suspected by bone marrow histology that demonstrated hypercellularity, granulocytic hyperplasia and mild megakaryocytic atypia and only mild reticuline fibrosis (MF-1). There were no MPN-driver markers (JAK2, CALR, MPL) revealed. Initial therapy with Hydroxyurea 2 g/day was started in Nov-2017. The re-work-up (morphological, cytogenetic, FISH and molecular) has been done in federal referral center in Nov-2017 but no signs of typical CML or Ph-MPN was detected. Mutation in exon 12 of ASXL1 gene was revealed in Jan-2018. After initial cytoreduction at follow-up in Feb-2018 mild leukocytosis (10.0-25.0x109/L) with shift to myelocytes and splenomegaly (+3 cm) was noted, severe fatigue and night sweats were still presented. Given the molecular results the target therapy with Ruxolitinib 15 mg BID was started since Feb-2018. The Ruxolitinib has given results with rapid resolution of constitutional symptoms, weight gain and complete CBC normalization during first month of therapy. At 3 months of treatment follow-up bone marrow histology showed hypocellularity and myeloid swelling. The first assessment of CSF3R gene in Russia on May-2018 has revealed the T618I mutation. Thus, the final diagnosis of aCML has been made (revealed mutation more related to CNL but WBC profile is consistent to aCML). The patient is still receiving Ruxolitinib therapy with complete clinical and hematologic response up to date. The search of unrelated donor was started. Conclusions. Nowadays diagnosis of aCML or CNL need to be established on thorough complex investigation. There is a need to get a widespread consensus guideline of aCML and CNL diagnosis and management and reclassification of these diseases in one common group. Disclosures No relevant conflicts of interest to declare.
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Dasgupta, Swati, Ujjal Ray, Soma Mukhopadhyay, Chinmoy Kumar Bose, Sanjoy Sarkar, Firoj Gharami, Subhasish Dey, Jayasri Basak, and Ashis Mukhopadhyay. "Imatinib Therapy for Chronic Myeloid Leukemia: An Experience From Eastern India." Blood 116, no. 21 (November 19, 2010): 4498. http://dx.doi.org/10.1182/blood.v116.21.4498.4498.
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Abstract Abstract 4498 Background: Chronic Myeloid Leukemia(CML) is an myloproliferative disorder characterized by the expansion of clone of hematopoietic cells that carries the Philadelphia chromosome(Ph).The Ph chromosome results from a reciprocal translocation between the long arms of chromosome 9 and 22,t(9;22) (q34;q11).The molecular consequence of this translocation is a fusion gene. Imatinib inhibits constitutively active BCR-ABL tyrosine kinase of Chronic Myeloid Leukemia (CML).This is a novel molecule, which inhibits the protein product of this fusion gene and hence has been used in the treatment of CML. We are now report 51 months of median follow-up data and focus on 645 number of patients who received Imatinib as a primary treatment from 2002 to 2010. Materials and Methods: We included total 645 patients of CML during the period of January 2002 to June 2010.The age range was 02–87 years with median age being 36±11.6 years. Among 645 patient 366 was male and 280 female. A total 645 patients 608was in chronic phase, 31 in accelerated phase and 5 patients had blast crisis at the time of presentation. At present the molecular status of the disease has been detected by RT PCR, Flowcytometry (By Fluorescence Activated Cell sorter, FACS), Karyotyping and FISH.As a runtime protocol we have used Imatinib as 400 mg/day as standard dose at chronic phase, 600 mg/day in accelerated phase and 800 mg/day in blast crisis.We have studied a comparative analysis of Hematological parameter values. Result: The best observed average rate of complete hematological response was 97%, complete cytogenetic response was 50%, complete molecular response 35% with partial response in 45% and poor response in 15%.After 1 year levels of BCR-ABL transcripts had fallen in 52% patients and after 4 years levels had fallen in 79%. Conclusion: At 51 months of median follow-up in our study, comparative analysis of haematological parameters like haemoglobin, Total Count, Platelet Count between patient and normal population revels that pre-treatment value against normal value is very significant. The post treatment value of the haematological parameters is very close to the normal values and hence it can be proved that Imatinib therapy is effective. We observed that Imatinib drug is tolarence in case of 90% patients and resistance in about 10 % patient. So, we can conclude that Imatinib is an effective and safe drug for CML patient. Disclosures: No relevant conflicts of interest to declare.
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Deininger, Michael W., Neil P. Shah, Jessica K. Altman, Ellin Berman, Ravi Bhatia, Bhavana Bhatnagar, Daniel J. DeAngelo, et al. "Chronic Myeloid Leukemia, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology." Journal of the National Comprehensive Cancer Network 18, no. 10 (October 2020): 1385–415. http://dx.doi.org/10.6004/jnccn.2020.0047.
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Chronic myeloid leukemia (CML) is defined by the presence of Philadelphia chromosome (Ph) which results from a reciprocal translocation between chromosomes 9 and 22 [t(9;22] that gives rise to a BCR-ABL1 fusion gene. CML occurs in 3 different phases (chronic, accelerated, and blast phase) and is usually diagnosed in the chronic phase. Tyrosine kinase inhibitor therapy is a highly effective first-line treatment option for all patients with newly diagnosed chronic phase CML. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with chronic phase CML.
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Fernandes, Adelina, Naranie Shanmuganathan, and Susan Branford. "Genomic Mechanisms Influencing Outcome in Chronic Myeloid Leukemia." Cancers 14, no. 3 (January 26, 2022): 620. http://dx.doi.org/10.3390/cancers14030620.
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Chronic myeloid leukemia (CML) represents the disease prototype of genetically based diagnosis and management. Tyrosine kinase inhibitors (TKIs), that target the causal BCR::ABL1 fusion protein, exemplify the success of molecularly based therapy. Most patients now have long-term survival; however, TKI resistance is a persistent clinical problem. TKIs are effective in the BCR::ABL1-driven chronic phase of CML but are relatively ineffective for clinically defined advanced phases. Genomic investigation of drug resistance using next-generation sequencing for CML has lagged behind other hematological malignancies. However, emerging data show that genomic abnormalities are likely associated with suboptimal response and drug resistance. This has already been supported by the presence of BCR::ABL1 kinase domain mutations in drug resistance, which led to the development of more potent TKIs. Next-generation sequencing studies are revealing additional mutations associated with resistance. In this review, we discuss the initiating chromosomal translocation that may not always be a straightforward reciprocal event between chromosomes 9 and 22 but can sometimes be accompanied by sequence deletion, inversion, and rearrangement. These events may biologically reflect a more genomically unstable disease prone to acquire mutations. We also discuss the future role of cancer-related gene mutation analysis for risk stratification in CML.
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Bajaj, Jeevisha, James Scott-Browne, Kyle Spinler, and Tannishtha Reya. "An In Vivo Genome-Wide CRISPR Screen Identifies Novel Dependencies for Blast Crisis Chronic Myelogenous Leukemia." Blood 132, Supplement 1 (November 29, 2018): 1727. http://dx.doi.org/10.1182/blood-2018-99-119178.
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Abstract Poorly differentiated aggressive myeloid diseases such as Acute Myelogenous Leukemia (AML) and blast crisis Chronic Myelogenous Leukemia (bcCML) are often resistant to standard therapy and associated with significantly poor survival in both children and adults. There is thus a significant need for a better understanding of the mechanisms that drive disease progression and for finding novel therapeutic targets. Thus, to determine the molecular effectors of myeloid leukemia growth in vivo, we carried out a genome-wide CRISPR/Cas9 dropout screen using the lentiviral Brie gRNA library. This library targets 19,674 genes, and has on average 3 gRNAs for each gene, and 1000 control non-targeting gRNAs. We carried out this whole-genome screen in a mouse model of Cas9+ blast crisis CML (bcCML) driven by BCR-ABL/ NUP98-HOXA9 since this represents a very aggressive phase of myeloid cancer where 90% of the leukemic blasts are undifferentiated and cancer stem cell-like. This in vivo screen led to the identification of 3636 genes essential for leukemic growth and propagation in the bone marrow of recipient mice, constituting pathways such as metabolism, protein translation and DNA replication. The genes that were significantly depleted included known drivers of myeloid cancer progression and regulators of myeloid cancer stem cells (for example, Brd4, Kdm1a, Pafah1b1/Lis1, Rptor), indicating that our screening strategy can successfully identify functional drivers of cancer growth. While intrinsic signals that drive myeloid cancer progression are well described, little is known about how interactions with the surrounding microenvironment can control leukemic growth and propagation. Our whole-genome screen identified ~130 cell surface genes that are significantly depleted in the bcCML stem cells transplanted in vivo. Since environmental factors commonly signal through receptors on the surface of leukemic cells, this subset is likely to include most, if not all, genetic effectors of niche driven signals required for in vivo growth and propagation of aggressive myeloid leukemia cells. Of these 130 genes, several have earlier been shown by us and others to be essential for myeloid cancer progression including Itgb1, Cxcr4 and Cd44. We are currently testing the functional contribution of novel candidate cell surface molecules, which can integrate signals from the environment, on the in vivo growth and progression of myeloid malignancies. We anticipate that these studies will provide a basis for testing antibody-mediated therapeutic inhibition of specific microenvironmental signals on myeloid leukemia growth and propagation. Disclosures No relevant conflicts of interest to declare.
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Panuzzo, Cristina, Lucrezia Pironi, Alessandro Maglione, Simone Rocco, Serena Stanga, Chiara Riganti, Joanna Kopecka, et al. "mTORC2 Is Activated under Hypoxia and Could Support Chronic Myeloid Leukemia Stem Cells." International Journal of Molecular Sciences 24, no. 2 (January 8, 2023): 1234. http://dx.doi.org/10.3390/ijms24021234.
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Hypoxia is a critical condition that governs survival, self-renewal, quiescence, metabolic shift and refractoriness to leukemic stem cell (LSC) therapy. The present study aims to investigate the hypoxia-driven regulation of the mammalian Target of the Rapamycin-2 (mTORC2) complex to unravel it as a novel potential target in chronic myeloid leukemia (CML) therapeutic strategies. After inducing hypoxia in a CML cell line model, we investigated the activities of mTORC1 and mTORC2. Surprisingly, we detected a significant activation of mTORC2 at the expense of mTORC1, accompanied by the nuclear localization of the main substrate phospho-Akt (Ser473). Moreover, the Gene Ontology analysis of CML patients’ CD34+ cells showed enrichment in the mTORC2 signature, further strengthening our data. The deregulation of mTOR complexes highlights how hypoxia could be crucial in CML development. In conclusion, we propose a mechanism by which CML cells residing under a low-oxygen tension, i.e., in the leukemia quiescent LSCs, singularly regulate the mTORC2 and its downstream effectors.
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Ali Mir, Ahmed, Abdur Rehman Mir, Uswah Rehmat, Ifra Shakoor, Farhan Amjad, Muhammad Khalid, Tauqeer H. Mallhi, and Talha Laique. "Treatment Responses in Patients with Chronic Myeloid Leukemia on Tyrosine Kinase Inhibitors (TKI) Therapy." Pakistan Journal of Medical and Health Sciences 15, no. 9 (September 30, 2021): 2358–60. http://dx.doi.org/10.53350/pjmhs211592358.
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Background: Chronic myeloid leukemia (CML) is a cancer of white blood cells results by the BCR-ABL translocation. Part of BCR gene from chromosome 22 is fused with ABL gene on chromosome 9. Aim: To observe percentage of patients achieving Cytogenetics response (CR), and Deep molecular response (DMR) in CML patients taking TKI (Imatinib and Nilotinib). Study Design: Retrospective Cohort study. Methodology: This study was conducted in 2018-2019 in about 198 CML patients to evaluate TKI therapy response and observation was based upon their Quantitative PCR test which gave percentage of BCR-ABL gene translocation in IU. Patients which were diagnosed with CML in 2016 and was regular in their treatment for about 2 years were included in the study. No intervention was given as in vivo study. Statistical analysis: Data analyzed by SPSS 25.0v. Results: Results showed that out of 198 CML patients, started on 1st line TKI (imatinib) 95 males (48%) and 103 females (52%) showed cytogenetic response at start of therapy and after 2 years of therapy 157 (79.3%) patient showed DMR. Conclusion: This study concluded that regular 2-year treatment of chronic CML patients with TKIs produced significant response in patients. Keywords: BCR-ABL Translocation, Cytogenetic Response, Major Molecular Response, Complete Molecular Response and Deep Molecular Response.
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Xue, Mengxing, Zhao Zeng, Qinrong Wang, Lijun Wen, Yi Xu, Jundan Xie, Qian Wang, Changgeng Ruan, Depei Wu, and Suning Chen. "Mutational Profiles during the Progression of Chronic Myeloid Leukemia." Blood 138, Supplement 1 (November 5, 2021): 3596. http://dx.doi.org/10.1182/blood-2021-154273.
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Abstract Background: Despite significant improvements in the prognosis of chronic myeloid leukemia (CML) achieved by targeted therapy with tyrosine kinase inhibitors (TKIs), a small proportion of cases may not respond to TKIs or may relapse after an initial response, and then progress from chronic phase (CP) to blastic crisis (BC), characterized by a dismal prognosis. It remained uncertain whether the genetic lesions in addition to the BCR-ABL1 fusion could predict clinical outcomes of CML in the TKI era. Aim: To study the mutational profiles at each stage of CML and the prognostic significance of somatic mutations in addition to the BCR-ABL1 fusion in the TKI era. Patients and Methods: We performed targeted sequencing in 81 CML patients chosen retrospectively. 10 patients had optimal response to TKIs by European LeukemiaNet criteria and maintained durable major molecular response more than 5 years. 71 patients had progressed to accelerated phase (AP) or BC, of whom 43 had sequencing performed at paired CP and AP/BC samples, 28 at AP or BC samples. Totally, we analyzed 53 CP, 20 AP, and 61 BC samples. The targeted resequencing gene panel, covering 386 genes which were recurrently mutated in hematologic malignancies, were performed on a HiSeq 4000 NGS platform (Illumina). Results: Among the 53 CP samples, 20 (37.7%) had mutations involving 14 genes, and the number of mutated genes in each patient was 0-3 (median 0). ASXL1 was the most commonly mutated gene, 10/53 (18.9%) patients had this mutation, followed by KMT2D (4/53, 7.5%), PC (2/53, 3.8%), ERBB4 (2/53, 3.8%). ASXL1 mutation mainly existed in 43 patients with progressed disease , while only one case carried this mutation in 10 patients responsive to TKIs (20.9% vs 10%). 17/20 (85%) AP samples (including 10 patients progressed to AP and the other 10 patients who eventually progressed to BC from AP ) carried mutations involving 18 genes, the number of mutated genes in each patient was 0-6 (median 1.5). ABL1 was the most commonly mutated gene, and 8/20 (40%) patients had this mutation. The second was the ASXL1 mutation, 7 (7/20, 35%) patients carried this mutation. The other genes mutated in more than 2 patients included BCORL1 (3/20, 15%), RUNX1 (2/20, 10%), PHF6 (2/20, 10%), KMT2D (2/20, 10%), ATM (2/20, 10%). 54/61 (88.5%) BC samples (44 with myeloid crisis, 14 with lymphoid crisis, 3 with mixed phenotypic crisis) carried mutations, involving 41 genes, and the number of mutated genes in each patient was 0-9 (median 2). Similar to the mutation status in AP, the most commonly mutated gene was also ABL1, 24/61 (39.3%) patients carried this gene mutation, followed by ASXL1 mutation (13/61, 21.3%), and the other genes were in order, RUNX1 (11/61, 18.0%), WT1 (8/61, 13.1%), GATA2 (6/61, 9.8%), MED12 (5/61, 8.2%), IDH1 (5/61, 8.2%), TP53 (4/61 , 6.6%), KMT2D (4/61, 6.6%), etc. (Figure 1A) Among all the samples, 34 nonsynonymous variants in the ASXL1 gene were identified in 31 samples of 21 patients ( 3 samples with two variants). All the variants were frameshift and nonsense mutations, localized at the last exon of the ASXL1 gene. 13/21 patients with ASXL1 mutations had multi-stage samples. The median VAF of the ASXL1 mutations in the advanced stage was 31.4% (0-47.0%), which was significantly higher than that in CP at diagnosis (7.0%, 0-27.2%, P=0.033). Most of the ASXL1 mutations detected in CP expanded at the advanced disease, and were accompanied with other additional gene abnormalities, such as ABL1, RUNX1 and WT1 mutations, with the VAF similar to or lower than that of the ASXL1 mutations. In a few cases, the ASXL1 mutant clones in the CP disappeared, suggesting that some ASXL1 mutations may be clonal hematopoiesis unrelated to disease progression.(Figure 1B) In order to evaluate the effects of ASXL1 mutations on sensitivity to TKIs in vitro. We co-expressed P210-BCR-ABL1 fusion and ASXL1 mutation (G646Wfs*12) in Ba/F3 cells. Compared to Ba/F3 cells co-expressing BCR-ABL1 fusion and ASXL1 mutation (Ba/F3-BA/As), Ba/F3-BCR-ABL1 cells without ASXL1 mutation (Ba/F3-BA/Ve) showed higher sensitivity to TKIs, including imatinib, dasatinib and nilotinib.(Figure 1C) Conclusions: These results demonstrated the genetic lesions accumulated during the progression of CML from CP to BC. ASXL1 mutations were the most common genetic lesion in CP at diagnosis and may confer a poor prognosis, as it reduced the sensitivity to TKIs. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
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Abramowitz, Julia, Tzahi Neuman, Rania Samman, Riki Perlman, and Dina Ben-Yehuda. "Mdm2 and Mdmx Are Not the Major Negative Regulators of the p53 Pathway in Myeloid Leukemias." Blood 114, no. 22 (November 20, 2009): 5046. http://dx.doi.org/10.1182/blood.v114.22.5046.5046.
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Abstract Abstract 5046 Mutations in the p53 tumor suppressor gene are rare in human hematological malignancies, suggesting that aberrant p53 function may be due to alterations in its regulatory pathways. p53 is negatively regulated by MDM2 through ubiquitin-dependent degradation and by Mdmx through inhibition of transcriptional function. There is little information on the expression of Mdm2 and Mdmx in most myeloid leukemias. We determined the gene expression and protein levels of Mdm2 and Mdmx in bone marrow samples of leukemia patients. We first performed quantitative evaluation of Mdm2 and Mdmx gene expression in bone marrow samples of 144 leukemic patients at the time of diagnosis: 29 de novo AML patients (AML, M0-M7, M3 excluded), 30 de novo AML M3 patients (APL), 39 therapy-related AML patients (t-AML, M0-M7, M3 included) and 46 CML chronic phase (CML-CP) patients in comparison to 35 normal bone marrow samples from Hodgkin's disease patients. Quantitative Real-Time PCR analysis showed no global statistically significant over expression of Mdm2 or Mdmx in any of the tested leukemias. However, a number of patients in both de novo and therapy-related AML had elevated levels of Mdm2 or Mdmx. Significant down regulation of Mdm2, Mdmx and a splicing variant of Mdmx lacking exon 6 (Mdmx-S) was observed in CML-CP. We next performed IHC staining, evaluated by semi-quantitative score, to examine the levels of Mdm2 and Mdmx protein expression in 151 leukemic patients at the time of diagnosis: 40 AML patients, 23 APL, 47 t-AML and 41 CML-CP patients in comparison to 58 normal bone marrow samples from Hodgkin's disease patients. Protein expression analysis also showed no global statistically significant over expression of Mdm2 in any of the tested leukemias. Nonetheless, a number of patients in both de novo and therapy-related AML had elevated levels of Mdm2 protein. Specifically, APL patients segregated into 2 groups: while half of the patients did not express the Mdm2 protein, the other half over-expressed Mdm2. A significant down-regulation of Mdmx was observed in APL. In summary, while in some leukemic patients Mdm2 and Mdmx might play a role in the regulation of p53, our quantitative analysis indicates that these negative regulators do not seem to provoke the inactivation of the p53 pathway in most myeloid leukemias patients. These findings have implications on the possible use of Mdm2 antagonists like nutlin-3 in myeloid leukemias. To the best of our knowledge this is the largest group of myeloid leukemia patients studied for Mdm2 and Mdmx expression. Disclosures No relevant conflicts of interest to declare.
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Spinler, Kyle, Tannishtha Reya, Jeevisha Bajaj, Takahiro Ito, Bryan Zimdahl, Armin Ahmadi, Claire Koechlein, et al. "Identification of Syndecan-1 As a Key Dependency of Myeloid Leukemia Growth and Dissemination." Blood 132, Supplement 1 (November 29, 2018): 3003. http://dx.doi.org/10.1182/blood-2018-99-115199.
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Abstract Intratumoral heterogeneity is a common feature of many myeloid leukemias and a significant reason for treatment failure and relapse. Thus identifying the cells responsible for residual disease and leukemia re-growth is critical to better understand how they are regulated. Here we show that a knock-in reporter mouse for the stem cell gene Musashi 2 (Msi2) allows identification of therapy resistant leukemia propagating cells in aggressive myeloid malignancies, and provides a new strategy for defining their core dependencies. Specifically, we carried out a high throughput screen using Msi2 reporter blast crisis chronic myeloid leukemia (bcCML) and identified syndecan-1 (Sdc1), a cell surface proteoglycan, as preferentially expressed in therapy resistant bcCML cells, and critical for bcCML function. Specifically, in Sdc1-/- mice, Sdc1 loss led to a defect in bcCML growth and propagation in vitro and in vivo, and markedly improved survival. Further, live imaging revealed that Sdc1 loss had a striking impact on the spatiotemporal dynamics of leukemia cells, impairing their localization, migration and systemic dissemination. Mechanistically, distinct elements of Sdc1 contributed to leukemia growth and dissemination, with the core protein alone being able to rescue the growth defect, but the heparin sulfate chains that mediate matrix attachment being needed for migration. These data present a new platform for delineating the biological underpinnings of leukemia stem cell function, and identify Sdc1 as a central regulator of leukemia stem cell growth and dissemination. Disclosures No relevant conflicts of interest to declare.
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Al-Amleh, Esraa K., Ola M. Al-Sanabra, Khalid M. Alqaisi, Moath Alqaraleh, Jumana Al-Nahal, Lama Hamadneh, Mohammed Imad Malki, and Jehad F. Alhmoud. "Investigation of the Effect of Imatinib and Hydroxyurea Combination Therapy on Hematological Parameters and Gene Expression in Chronic Myeloid Leukemia (CML) Patients." Journal of Clinical Medicine 11, no. 17 (August 24, 2022): 4954. http://dx.doi.org/10.3390/jcm11174954.
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(1) Background: Chronic myeloid leukemia is defined as the neoplastic development of mostly myeloid cells in the bone marrow. Several treatments, including chemotherapy, radiation, hormone treatment, and immunological therapy, can be used to control this condition. The therapeutic impact on leukemic individuals varies, and the response to therapy varies between patients due to disease heterogeneity. The primary goal of this study is to compare the effects of single and Imatinib (IM) and Hydroxyurea (HU) combined treatment on hematological parameters and gene expression in CML patients. (2) Methods: This study was conducted on 51 patients, with chronic myeloid leukemia, who were admitted to Al-Basher hospital in Amman, Jordan, for follow-up. Their hematological parameters were checked and gene expression was measured for (BCL2, PP2A, CIP2A, and WT1). (3) Results: The BCL2 gene was found to be less expressed in both IM and (HU + IM) treatments as compared to the HU group alone, while PP2A gene expression was raised. Such a thing indicates that the outcome of the combined therapy method is not ideal, since PP2A activation causes CML cells to move toward the blast crisis stage. Furthermore, CIP2A gene expression revealed that IM and (HU + IM) had the same therapeutic effect and were more successful in CML patients than HU alone. With regards to the treatment effect on hematological parameters, notably in CML patients in later stages, the combination therapy (HU + IM) raised lymphocyte count, indicating a greater response to the treatment. When compared to single medicines, the combination treatment reduced the proportion of neutrophils to normal reference ranges. Platelet counts, on the other hand, dramatically decreased in both IM and (HU + IM). (4) Conclusion: Because the studied genes (BCL2, PP2A, CIP2A, and WT1) are participating in cell proliferation and death, the findings show that the examined genes are significant to understand the efficacy of various therapies. Furthermore, it was found that there was a clear effect of the clinic-based strategic treatment on hematological indicators such as WBCs, lymphocytes, neutrophils, and platelet counts.
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Holyoake, Tessa L., and David Vetrie. "The chronic myeloid leukemia stem cell: stemming the tide of persistence." Blood 129, no. 12 (March 23, 2017): 1595–606. http://dx.doi.org/10.1182/blood-2016-09-696013.
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Abstract Chronic myeloid leukemia (CML) is caused by the acquisition of the tyrosine kinase BCR-ABL1 in a hemopoietic stem cell, transforming it into a leukemic stem cell (LSC) that self-renews, proliferates, and differentiates to give rise to a myeloproliferative disease. Although tyrosine kinase inhibitors (TKIs) that target the kinase activity of BCR-ABL1 have transformed CML from a once-fatal disease to a manageable one for the vast majority of patients, only ∼10% of those who present in chronic phase (CP) can discontinue TKI treatment and maintain a therapy-free remission. Strong evidence now shows that CML LSCs are resistant to the effects of TKIs and persist in all patients on long-term therapy, where they may promote acquired TKI resistance, drive relapse or disease progression, and inevitably represent a bottleneck to cure. Since their discovery in patients almost 2 decades ago, CML LSCs have become a well-recognized exemplar of the cancer stem cell and have been characterized extensively, with the aim of developing new curative therapeutic approaches based on LSC eradication. This review summarizes our current understanding of many of the pathways and mechanisms that promote the survival of the CP CML LSCs and how they can be a source of new gene coding mutations that impact in the clinic. We also review recent preclinical approaches that show promise to eradicate the LSC, and future challenges on the path to cure.
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Fischer, Konstanze, Stefan Fröhling, Stephen W. Scherer, Jill McAllister Brown, Claudia Scholl, Stephan Stilgenbauer, Lap-Chee Tsui, Peter Lichter, and Hartmut Döhner. "Molecular Cytogenetic Delineation of Deletions and Translocations Involving Chromosome Band 7q22 in Myeloid Leukemias." Blood 89, no. 6 (March 15, 1997): 2036–41. http://dx.doi.org/10.1182/blood.v89.6.2036.
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Abstract Loss of chromosome 7 (−7) or deletion of its long arm (7q−) are recurring chromosome abnormalities in myeloid disorders, especially in therapy-related myelodysplastic syndrome (t-MDS) and acute myeloid leukemia (t-AML). The association of −7/7q− with myeloid leukemia suggests that these regions contain a novel tumor suppressor gene(s) whose loss of function contributes to leukemic transformation or tumor progression. Based on chromosome banding analysis, two critical regions have been identified: one in band 7q22 and a second in bands 7q32-q35. We analyzed bone marrow and blood samples from 21 patients with myeloid leukemia (chronic myeloid leukemia, n = 2; de novo MDS, n = 4; de novo AML, n = 13; t-AML, n = 2) that on chromosome banding analysis exhibited deletions (n = 19) or reciprocal translocations (n = 2) of band 7q22 using fluorescence in situ hybridization. As probes, we used Alu-polymerase chain reaction products from 22 yeast artificial chromosome (YAC) clones that span chromosome bands 7q21.1-q32, including representative clones from a panel of YACs recognizing a contiguous genomic DNA fragment of 5 to 6 Mb in band 7q22. In the 19 cases with deletions, we identified two distinct commonly deleted regions: one region within band 7q22 was defined by the two CML cases; the second region encompassed a distal part of band 7q22 and the entire band 7q31 and was defined by the MDS/AML cases. The breakpoint of one of the reciprocal translocations was mapped to 7q21.3, which is centromeric to both of the commonly deleted regions. The breakpoint of the second translocation, which was present in unstimulated bone marrow and phytohemagglutinin-stimulated blood of an MDS patient, was localized to a 400-kb genomic segment in 7q22 within the deletion cluster of the MDS/AML cases. In conclusion, our data show marked heterogeneity of 7q22 deletion and translocation breakpoints in myeloid leukemias, suggesting the existence of more than one pathogenetically relevant gene.
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Imataki, Osamu, Tomoya Ishida, Hiroyuki Kubo, Makiko Uemura, Yasuhito Nanya, Kimihiro Kawakami, Seishi Ogawa, and Norimitsu Kadowaki. "A Case of Tyrosine Kinase Inhibitor-Resistant Chronic Myeloid Leukemia, Chronic Phase with ASXL1 Mutation." Case Reports in Oncology 13, no. 1 (April 22, 2020): 449–55. http://dx.doi.org/10.1159/000506452.
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Hematological malignancies, including chronic myeloid leukemia (CML), exhibit ASXL1 mutations; however, the function and molecular mechanism of these mutations remain unclear. ASXL1 was originally identified as tumor suppressor gene, in which loss of function causes myelodysplastic syndrome (MDS). ASXL1 mutations are common and associated with disease progression in myeloid malignancies including MDS, acute myeloid leukemia, and similarly in CML. In MDS, ASXL1 mutations have been associated with poor prognosis; however, the impact of ASXL1 mutations in CML has not been well described. A 31-year-old male was diagnosed as CML-chronic phase (CP). Laboratory findings showed a white blood cell count of 187,200/µL, with asymptomatic splenomegaly. Blast count was 5.0% in peripheral blood and 7.3% in bone marrow. There was no additional chromosomal abnormality except for t(9;22)(q34;q11.2) by chromosomal analysis. At onset, the Sokal score was 1.4, indicating high risk. The patient received tyrosine kinase inhibitor (TKI) therapy, comprising nilotinib ∼600 mg/day, bosutinib ∼600 mg/day, ponatinib ∼45 mg/day, and dasatinib ∼100 mg/day. Nevertheless, after 1.5 years of continuous TKI therapy, the best outcome was a hematological response. Although additional chromosomal aberrations and ABL1 kinase mutations were analyzed repeatedly before and during TKI therapy, known genetic abnormalities were not detected. Thereafter, the patient underwent bone marrow transplantation from an HLA 7/8 matched unrelated donor (HLA-Cw 1 locus mismatch, graft-versus-host direction). The patient achieved neutrophil engraftment, 18 days after transplantation, leading to complete remission with an undetectable level of BCR-ABL1 mRNA. The patient, however, died from graft-versus-host disease and thrombotic microangiopathy after 121 days. Gene sequence analysis of his CML cell before stem cell transplantation revealed ASXL1 mutations. Physiologically, ASXL1 contributes to epigenetic regulation. In the CML-CP patient in this case report, ASXL1 mutation conferred resistance to TKI through obscure resistance mechanisms. Even though a molecular mechanism for TKI resistance in ASXL1 mutation in CML has remained obscure, epigenetic modulation is a plausible mode of CML disease progression. The clinical impact including prognosis of ASXL1 for CML is underscored. And the treatment strategy of CML with ASXL1 mutation has not been established. A discussion of this case was expected to facilitate treatment options.
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Datoguia, Tarcila S., Hugo R. C. Silva, Amauri M. C. R. Junior, José Salvador Oliveira, and Monika Conchon. "Drug Toxicities in Second-Line Treatment of Chronic Myeloid Leukemia." Blood 126, no. 23 (December 3, 2015): 5173. http://dx.doi.org/10.1182/blood.v126.23.5173.5173.
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Abstract Introduction Chronic myeloid leukemia (CML) is known to be a myeloproliferative neoplasm that involves a genetic abnormality defined as Philadelphia chromosome. Part of chromosome 9 becomes attached to chromosome 22, forming the BCR-ABL fusion gene, which is an oncogenic tyrosine kinase. The rise of the tyrosine kinase inhibitors (TKIs) has transformed the outcome of CML. Imatinib was the first TKI approved for treating patients diagnosed with CML in 2001. Dasatinib and Nilotinib were accredited as second-line therapy in 2006 and 2007, respectively, for patients who had failed previous therapy. Although these new drugs improved response compared with imatinib, they also have important side effects that can lead to non-adherence to treatment. Given the importance to maintain regular treatment to avoid disease progression, this paper aims to discuss the drug toxicities in patients undergoing second-line therapy. Patients and methods This study was an observational analysis using medical records in Santa Marcelina Hospital, a public service located in São Paulo, Brazil. Results A total of 58 CML patients taking second-line therapy were included, 28 with dasatinib and 30 with nilotinib. In dasatinib group, only 3 patients were diagnosed accelerated phase and each one had different side effects, as hematological toxicity, pleural effusion and ulcerative colitis. Of 25 chronic phase patients taking dasatinib, 12 (48%) presented with clinical and laboratorial abnormalities: 3.5% had hematological toxicity (2% with severe bleeding), 4% had cutaneous rash, 10.7% with ulcerative colitis (confirmed in bowel biopsy) and 18% developed pleural effusion. 25% of all dasatinib patient with side effects lost molecular response and started a third TKI. In nilotinib cohort, 7 patients were diagnosed with CML accelerated phase and only two developed liver toxicity. 23 patients were chronic phase and 60% presented with several side effects: 3% hypertriglyceridemia, 6% had hematological toxicity, 6% with dyspepsia, 10% had cutaneous rash and 27% presented with higher liver transaminase. 7% of all nilotinib patients who developed side effects lost molecular response and had to discontinue therapy. Discussion Several examples of side effects can be described with all TKI including cytopenias, fatigue, pain, fluid retention, GI disorders, skin complains, cardiac and liver toxicities but grade 3-4 occurs in less than 2-3% of patients as Jabour et al reported. Despite of important adverse effects, dasatinib and nilotinib induce rapid and durable hematologic and cytogenetic response. In general, the most related toxicities are self-limited and manageable as Kantarjian related. Comparisons between these two second-line therapy using intolerance criteria can be difficult to represent because studies published until now have two different types of population in terms of cytogenetic response achieved previously with imatinib, for example. So, to have a successful treatment, it is important to consider other variables as comorbidities and mutational status as referred Mathisen et al. Individualized risk assessment, between CML and patients characteristics, should influence treatment choices and clinical management. In conclusion, the efficacy and safety of dasatinib and nilotinib have been confirmed by long-term outcome. Clearly these drugs have unique pharmacologic profiles and response patterns in every single patient, but the goal of treating these patients is the correct management of adverse events without losing molecular response. Disclosures No relevant conflicts of interest to declare.
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Kartthik, S., Prakas K. Mandal, and Saleh Mohammed Abdullah. "An Unusual Cause of Bleeding in a Patient with Chronic Myeloid Leukemia Chronic Phase." Case Reports in Hematology 2019 (September 9, 2019): 1–5. http://dx.doi.org/10.1155/2019/5674193.
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Chronic myelogenous leukemia (CML) is a clonal myeloproliferative neoplasm (MPN) characterized by dysregulated and uncontrolled proliferation of mature and maturing granulocytes with normal differentiation. A genetic hallmark of CML is the presence of the fusion gene product BCR-ABL. Bleeding diathesis in CML patients is rare (<10%) and primarily caused by acquired platelet dysfunction. We report a rare case of an adult CML chronic phase patient who presented with spontaneous muscle hematoma due to acquired Glanzmann’s thrombasthenia (GT). On laboratory workup, a GT was confirmed along with the diagnosis of CML in chronic phase. The muscle hematoma was completely resolved following imatinib therapy. The present case demonstrates that bleeding is a complication of MPNs and highlights the importance of both acquired GT diagnosis to determine the cause of bleeding in CML and of prompt treatment with imatinib to reverse this condition.
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Hunger, SP, DC Tkachuk, MD Amylon, MP Link, AJ Carroll, JL Welborn, CL Willman, and ML Cleary. "HRX involvement in de novo and secondary leukemias with diverse chromosome 11q23 abnormalities [see comments]." Blood 81, no. 12 (June 15, 1993): 3197–203. http://dx.doi.org/10.1182/blood.v81.12.3197.3197.
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Abstract Chromosome band 11q23 is a site of recurrent translocations and interstitial deletions in human leukemias. Recent studies have shown that the 11q23 gene HRX is fused to heterologous genes from chromosomes 4 or 19 after t(4;11)(q21;q23) and t(11;19)(q23;p13) translocations to create fusion genes encoding proteins with structural features of chimeric transcription factors. In this report, we show structural alterations of HRX by conventional Southern blot analyses in 26 of 27 de novo leukemias with cytogenetically diverse 11q23 abnormalities. The sole case that lacked HRX rearrangements was a t(11;17)-acute myeloid leukemia with French-American-British M3-like morphology. We also analyzed 10 secondary leukemias that arose after therapy with topoisomerase II inhibitors and found HRX rearrangements in 7 of 7 with 11q23 translocations, and in 2 of 2 with unsuccessful karyotypes. In total, we observed HRX rearrangements in 35 leukemias involving at least nine distinct donor loci (1q32, 4q21, 6q27, 7p15, 9p21–24, 15q15, 16p13, and two 19p13 sites). All breakpoints localized to an 8-kb region that encompassed exons 5–11 of HRX, suggesting that fusion proteins containing similar portions of HRX may be consistently created in leukemias with 11q23 abnormalities. We conclude that alteration of HRX is a recurrent pathogenetic event in leukemias with 11q23 aberrations involving many potential partners in a variety of settings including acute myeloid leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia in blast crisis, and topoisomerase II inhibitor- induced secondary leukemias of both the myeloid and lymphoid lineages.
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Hunger, SP, DC Tkachuk, MD Amylon, MP Link, AJ Carroll, JL Welborn, CL Willman, and ML Cleary. "HRX involvement in de novo and secondary leukemias with diverse chromosome 11q23 abnormalities [see comments]." Blood 81, no. 12 (June 15, 1993): 3197–203. http://dx.doi.org/10.1182/blood.v81.12.3197.bloodjournal81123197.
Full textAbstract:
Chromosome band 11q23 is a site of recurrent translocations and interstitial deletions in human leukemias. Recent studies have shown that the 11q23 gene HRX is fused to heterologous genes from chromosomes 4 or 19 after t(4;11)(q21;q23) and t(11;19)(q23;p13) translocations to create fusion genes encoding proteins with structural features of chimeric transcription factors. In this report, we show structural alterations of HRX by conventional Southern blot analyses in 26 of 27 de novo leukemias with cytogenetically diverse 11q23 abnormalities. The sole case that lacked HRX rearrangements was a t(11;17)-acute myeloid leukemia with French-American-British M3-like morphology. We also analyzed 10 secondary leukemias that arose after therapy with topoisomerase II inhibitors and found HRX rearrangements in 7 of 7 with 11q23 translocations, and in 2 of 2 with unsuccessful karyotypes. In total, we observed HRX rearrangements in 35 leukemias involving at least nine distinct donor loci (1q32, 4q21, 6q27, 7p15, 9p21–24, 15q15, 16p13, and two 19p13 sites). All breakpoints localized to an 8-kb region that encompassed exons 5–11 of HRX, suggesting that fusion proteins containing similar portions of HRX may be consistently created in leukemias with 11q23 abnormalities. We conclude that alteration of HRX is a recurrent pathogenetic event in leukemias with 11q23 aberrations involving many potential partners in a variety of settings including acute myeloid leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia in blast crisis, and topoisomerase II inhibitor- induced secondary leukemias of both the myeloid and lymphoid lineages.
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Borisevich, M. V., and T. V. Savitskaya. "F359C mutation of the BCR-ABL1 gene in adolescent with chronic myeloid leukemia. Case report." Russian Journal of Pediatric Hematology and Oncology 6, no. 2 (April 24, 2019): 72–75. http://dx.doi.org/10.21682/2311-1267-2019-6-2-72-75.
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Chronic myeloid leukemia (CML) in children is rare, less than 3 % of all cases of leukemia in pediatric practice. Along with the successes achieved in the treatment of CML with imatinib, it’s necessary to study of molecular factors in predicting resistance to therapy. According to the literature, about 30 % of adult patients with imatinib resistance have point mutations in the kinase domain of BCR-ABL1 gene. The number of reports about mutation spectrum of the BCR-ABL1 gene in children with resistant forms of CML is limited. This article describes the clinical case of secondary resistance to imatinib in a 15-year-old girl with the F359C mutation of BCR-ABL1 gene and a review of the literature.
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Horne, Gillian A., Heather Morrison, Victoria Campbell, Ross Kinstrie, Jennifer Cassels, Alan Hair, David Vetrie, Helen Wheadon, Tessa L. Holyoake, and Mhairi Copland. "Notch Pathway Activation Targets Leukemic Stem Cells in Chronic-Phase Chronic Myeloid Leukemia (CP-CML)." Blood 128, no. 22 (December 2, 2016): 3057. http://dx.doi.org/10.1182/blood.v128.22.3057.3057.
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Abstract The phenomenon of disease persistence in CP-CML under therapy with ABL kinase inhibitors suggests BCR-ABL-independent mechanisms are being exploited to sustain the survival of leukemic stem cells (LSC). Many self-renewal pathways have been implicated in their survival. The role of Notch signalling has yet to be fully elucidated, with conflicting reports suggesting a variety of roles in myeloid disease. The aims of this project were (1) to assess the expression and functional role of the Notch pathway in primary CD34+CP-CML cells, and (2) to assess differences in the functional role between stem and progenitor subpopulations in disease maintenance and progression. We hypothesized that Notch activation would have different functional effects dependent on disease phase and cell maturity. Extensive analysis of existing microarray datasets, GSE47927 and E-MTAB2481, comparing CP-CML LSCs to normal HSCs, showed that the Notch pathway was downregulated in CP-CML (p=0.05, both). To validate these results, using Fluidigm technology, mRNA expression of untreated CD34+ CP-CML cells (n=24) was compared to normal bone marrow CD34+ cells (n=5). The Notch pathway was silenced in untreated CP-CML, as evidenced by downregulation of Notch target genes, HES1 (p<0.0001) and HIF1A (p=0.0029). The Notch receptor, NOTCH2, was significantly upregulated (p<0.0001) in the same samples. This was confirmed with immunofluorescence (IF) of the full-length receptor (n=5). The activated form of the Notch receptor, val1744, was absent on CD34+CP-CML cells by either IF or Western blotting (n=3), nor was there any significant change in functional analyses of CP-CML cells treated with the pharmacological Notch inhibitor, DAPT (n=5). These results support our hypothesis that the pathway is silenced in CP-CML. As CD34+ CP-CML cells abundantly express NOTCH2, we investigated whether the pathway could be reactivated through exogenous stimulation upon ligand binding. An OP9 co-culture system was utilized to allow for overexpression of Notch ligands, DLL1 or JAG1, using OP9GFP as control stroma. Compared to non-stromal conditions, culturing over 7 days on OP9GFP led to a significant increase in growth (p=0.02, n=5). The overexpression of JAG1 led to a further increase compared to OP9GFP (p=0.002). We confirmed that activation of the pathway was through JAG1, and not DLL1, by utilizing DAPT, where we observed a significant decrease in live cell counts within the OP9GFP (p=0.01) and OP9JAG1 (p=0.018) experimental arms. Upregulation of the pathway was confirmed with increased expression of HES1 at the gene level (n=4, p=0.001), andval1744 protein by IF (n=5). CP-CML samples (n=3) were FACS-sorted into Lin-CD34+38+ and Lin-CD34+38- populations to assess for functional variation in stem and progenitor populations. Following 7 days in culture, live cell counts showed a significant increase in Lin-CD34+38+ cells on OP9JAG1 co-culture (p=0.04). There was a decrease in cell growth of Lin-CD34+38- cells in the same experimental conditions (p=0.02), with an associated increased trend in late apoptotic cells (ns). We hypothesized that Notch activation would have a toxic influence on an immature CML LSC population. LTCIC assays showed a significant decrease in colonies for CD34+38-cells co-cultured with OP9JAG1 for 7 days (p<0.05, n=8). In myeloid BP (n=4), in similar experiments, sorted Lin-CD34+38+ and Lin-CD34+38- populations did not demonstrate this functional profile of Notch activation, despite an upregulation in NOTCH2 receptor expression compared to normal (n=11) (p=0.0035). To investigate this further, we sorted CP (n=12), myeloid BP (n=11), and lymphoid BP (n=5) into stem and progenitor populations, before undertaking quantitative PCR of 90 self-renewal gene components of Wnt, Notch, Hedgehog, and BMP pathways. The self-renewal pathways were highly deregulated between CP and BP. The differential gene expression in lymphoid BP was comparable to myeloid BP. There was statistically significant upregulation in Wnt components in myeloid BP compared to CP, particularly TCF7(p=0.0011). We hypothesize that Wnt upregulation is preventing Notch activation in myeloid BP-CML. Taken together, our results identify that Notch activation may be a therapeutic approach to target CP-CML LSCs. However, this cannot be translated to myeloid BP, highlighting the complexity of self-renewal pathway interaction. Disclosures Wheadon: GlaxoSmithKline: Research Funding. Holyoake:Novartis: Honoraria, Research Funding; Bristol Myers Squib: Honoraria, Research Funding. Copland:ARIAD: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Shire: Honoraria; Amgen: Honoraria; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.
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Ali Hailan, Yousef Mohammed, Deena Mudawi, and Mohamed A. Yassin. "Chronic Myeloid Leukemia in a Patient with Hepatitis B Virus Infection: A Case Report." Case Reports in Oncology 14, no. 2 (June 24, 2021): 1004–9. http://dx.doi.org/10.1159/000516747.
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Chronic myeloid leukemia (CML) is a myeloproliferative disorder diagnosed by demonstrating the Philadelphia chromosome (Ph) or the BCR-ABL fusion gene. Tyrosine kinase inhibitors (TKIs) are the standard of therapy. There are increasing reports of hepatitis B virus reactivation (HBVr) in patients on this treatment. We report a case of a 46-year-old male patient diagnosed to have CML in the chronic phase and resolved hepatitis B infection. He was treated with imatinib as upfront therapy for CML and with lamivudine as prophylaxis against HBVr. The patient tolerated both treatments well with no adverse effects. The aim is to address the deficiencies in the literature in regard to managing these patients, prevention, and follow-up.
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Stock, W., C. A. Westbrook, B. Peterson, D. C. Arthur, T. P. Szatrowski, R. T. Silver, D. A. Sher, et al. "Value of molecular monitoring during the treatment of chronic myeloid leukemia: a Cancer and Leukemia Group B study." Journal of Clinical Oncology 15, no. 1 (January 1997): 26–36. http://dx.doi.org/10.1200/jco.1997.15.1.26.
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PURPOSE Disappearance of the Philadelphia chromosome during treatment for chronic myeloid leukemia (CML) has become an important therapeutic end point. To determine the additional value of molecular monitoring during treatment for CML, we performed a prospective, sequential analysis using quantitative Southern blot monitoring of BCR gene rearrangements of blood and marrow samples from Cancer and Leukemia Group B (CALGB) study 8761. PATIENTS AND METHODS Sixty-four previously untreated adults with chronic-phase CML who were enrolled onto CALGB 8761, a molecular-monitoring companion study to a treatment study for adults with chronic-phase CML (CALGB 9013). Treatment consisted of repetitive cycles of interferon alfa and low-dose subcutaneous cytarabine. Blood and marrow Southern blot quantitation of BCR gene rearrangements was compared with marrow cytogenetic analysis before the initiation of treatment and of specified points during therapy. Reverse-transcriptase polymerase chain reaction (RT-PCR) analysis was performed to detect residual disease in patients who achieved a complete response by Southern blot or cytogenetic analysis. RESULTS Quantitative molecular monitoring by Southern blot analysis of blood samples was found to be equivalent to marrow monitoring at all time points. Twelve of 62 (19%) follow-up samples studied by Southern blot analysis had a complete loss of BCR gene rearrangement in matched marrow and blood specimens. Southern blot monitoring of blood samples was also found to be highly correlated to marrow cytogenetic evaluation at all points, although there were four discordant cases in which Southern blot analysis of blood showed no BCR gene rearrangement, yet demonstrated from 12% to 20% Philadelphia chromosome-positive metaphase cells in the marrow. RT-PCR analysis detected residual disease in five of six patients in whom no malignant cells were detected using Southern blot or cytogenetic analyses. CONCLUSION Quantitative Southern blot analysis of blood samples may be substituted for bone marrow to monitor the response to therapy in CML and results in the need for fewer bone marrow examinations. To avoid overestimating the degree of response, marrow cytogenetic analysis should be performed when patients achieve a complete response by Southern blot monitoring. This approach provides a rational, cost-effective strategy to monitor the effect of treatment of individual patients, as well as to analyze large clinical trials in CML.
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Duong, Chinh Q., Trang T. Nguyen, Lam V. Nguyen, Huy Q. Pham, Hien T. T. Trinh, Hoang C. Tran, Tuong Q. Le, et al. "ID: 2036 Next-generation sequencing to evaluate frequency of BCR-ABL1 kinase domain Imatinib-resistance mutations." Biomedical Research and Therapy 4, S (September 5, 2017): 67. http://dx.doi.org/10.15419/bmrat.v4is.275.
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Chronic myeloid leukemia is a clonal myeloproliferative neoplasm, characterized by the presence of chromosomal translocation t(9; 22)(q34; q11). This is found in over 95% of the cases and results in the BCR-ABL1 fusion gene with high tyrosine kinase activity. During the last decades, imatinib and other generation of tyrosine kinase inhibitors have been used effectively for target therapy of the disease. However, many of the drug resistance cases have been reported recently, due to the mutation within kinase domain of the BCR-ABL1 fusion gene. In this work, we performed a retrospective study of 141 imatinib-resistance chronic myeloid leukemia patients to analyze kinase domain mutation by deep sequencing. Another group of 20 untreated patients were added as control. RNA from bone marrow cells was extracted and deeply sequenced utilizing Illumina MiSeq. Bioinformatics pipeline was applied for variant calling and annotation. And the Sanger sequencing was used to validate those mutations. The results showed that nearly one-fourth of patients harboring mutations that resist to Imatinib, among those, Y253F/H, M351T, G250E, F359V/I and M244V were the most frequent mutations. There were also a number of samples harboring multiple substitutions and new variations. Thus, Next-generation sequencing could be the sensitive and effective method to detect kinase domain mutation and our results could provide further information about the drug-resistance mutation in chronic myeloid leukemia.
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Scheller, Marina, Jörg Schönheit, Karin Zimmermann, Ulf Leser, Frank Rosenbauer, and Achim Leutz. "Cross talk between Wnt/β-catenin and Irf8 in leukemia progression and drug resistance." Journal of Experimental Medicine 210, no. 11 (October 7, 2013): 2239–56. http://dx.doi.org/10.1084/jem.20130706.
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Progression and disease relapse of chronic myeloid leukemia (CML) depends on leukemia-initiating cells (LIC) that resist treatment. Using mouse genetics and a BCR-ABL model of CML, we observed cross talk between Wnt/β-catenin signaling and the interferon-regulatory factor 8 (Irf8). In normal hematopoiesis, activation of β-catenin results in up-regulation of Irf8, which in turn limits oncogenic β-catenin functions. Self-renewal and myeloproliferation become dependent on β-catenin in Irf8-deficient animals that develop a CML-like disease. Combined Irf8 deletion and constitutive β-catenin activation result in progression of CML into fatal blast crisis, elevated leukemic potential of BCR-ABL–induced LICs, and Imatinib resistance. Interestingly, activated β-catenin enhances a preexisting Irf8-deficient gene signature, identifying β-catenin as an amplifier of progression-specific gene regulation in the shift of CML to blast crisis. Collectively, our data uncover Irf8 as a roadblock for β-catenin–driven leukemia and imply both factors as targets in combinatorial therapy.
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Martynkevich, Irina, Vasily Shuvaev, Ekaterina Petrova, Lyubov Polushkina, Lyudmila Martynenko, Marina Ivanova, Natalya Cybakova, et al. "Early Molecular Response in Chronic Myeloid Leukemia Patients Predicts Future Response Status." Blood 124, no. 21 (December 6, 2014): 5529. http://dx.doi.org/10.1182/blood.v124.21.5529.5529.
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Abstract Objectives and background: The level of early MR is important for the optimization of therapy and making a decision to a switch to 2nd line therapy in patients (pts) who have not achieved an optimal response (OR). According to the recent recommendations at definition of OR on CML therapy, pts must have the level of BCR-ABL transcript gene at 10% or less and Ph-positive cells 35% or less at 3 months. But, in half of all cases of pts with BCR-ABL >10% at 3 months progression events happen between 3 and 6 months. The goal of our research was to investigate the prognostic impact of a large BCR-ABL transcript amount at 3 months on the subsequent response and the long-term outcome of CML pts treated frontline with IM. Methods: We have examined 185 pts, who have got IM from January 2010 up to the present. Molecular monitoring has been done regularly in all patients according to ELN recommendations. Median age was 49 years. All pts were in CP. BCR-ABL transcript levels were assessed by real-time quantitative PCR. Results: In our study 54% (100/185 cases) of pts achieved the optimal response with BCR-ABL transcript levels ≤10% at 3 months, 50,3% (93/185 cases) did it - with BCR-ABL transcript levels ≤1% at 6 months, and only 18% achieved the optimal response at 12 months. The comparative analysis has shown statistical differences in all characteristics in 2 groups of pts, who either achieved or not the optimal response at 3 months. Pts with BCR-ABL transcript levels ≤10% more often achieved CCgR at 6 months (g=0,0000), CCgR during all period (g=0,0004), MMR at 12 months (g=0,0000), MMR during all period (g=0,0012) and MR4 during all period (g=0,0000), pts had londer event-free (g=0,0432) and overall (g=0,0279) 4-year survival. Figure 1 Figure 1. In our center we have switched 6 patients to the 2nd TKI - those who didn't achieve the optimal response at 3 months. The switching showed the positive influence on loss level expression of BCR-ABL gene in 5 out of 6 patients. After that all patients achieved the optimal response in the future. For example, we had one patient with failure of IM at 3 months. We switched him the therapy to NI in 5 months after the diagnosis. As a result the patient achieved CCgR at 1,5 months, and the deep molecular response 4,5 log at 3 months. Conclusions: Early and deep responses to TKIs are predictive of long-term response and favorable survival outcomes. 3-month reduction in BCR-ABL transcript levels to >10% is a factor of bad effectiveness of TKI therapy and requires switching to the 2nd TKI. Timely switching to the 2nd TKIs allows us to achieve an optimal response in CML patients with level BCR-ABL >10% at 3 months. References: Timothy P. Hughes, Giuseppe Saglio, Hagop M. Kantarjian et al. Early molecular response predicts outcomes in patients with chronic myeloid leukemia in chronic phase treated with frontline nilotinib or imatinib. Blood, 27 February 2014 x Volume 123, Number 9. Disclosures No relevant conflicts of interest to declare.
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Chien, Kelly S., Rashmi Kanagal-Shamanna, Kiran Naqvi, Koji Sasaki, Yesid Alvarado, Koichi Takahashi, Tapan M. Kadia, et al. "The Impact of PHF6 Mutations in Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, and Acute Myeloid Leukemia." Blood 134, Supplement_1 (November 13, 2019): 1436. http://dx.doi.org/10.1182/blood-2019-131188.
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Background: Plant homeodomain finger 6 (PHF6) is a tumor suppressor gene involved in chromatin-mediated transcriptional regulation. It has been found to be frequently mutated in lymphoid leukemias, especially T-cell acute lymphoblastic leukemia and mixed phenotypic acute leukemia, and mutated in approximately 3% of myeloid leukemias, but its role in myeloid neoplasms is less well-characterized. We consequently investigated the impact of PHF6 mutations in patients (pts) with myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), and acute myeloid leukemia (AML). Methods: We retrospectively evaluated all pts with MDS, CMML, or AML treated between 2017-2019. Patient characteristics and bone marrow data, including cytogenetic and next generation sequencing information, were assessed. Genomic DNA was extracted from whole bone marrow aspirate samples and subject to 81-gene target PCR-based sequencing using a next generation sequencing (NGS) platform. Response assessment was performed following 2006 International Working Group (IWG) criteria for pts with MDS or CMML and by 2003 IWG criteria for pts with AML. The Kaplan-Meier product limit method was used to estimate survival outcomes for each clinical/demographic factor. Univariate Cox proportional hazards regression was used to identify any association with each of the variables and survival outcomes. Results: A total of 56 pts with PHF6 mutations were identified: 21 with MDS, 6 with CMML, and 29 with AML (Figure A). Among these, 31 pts were male (55.4%). A total of 13 pts (61.9%) with MDS, 5 (83.3%) with CMML, and 12 (41.4%) with AML had normal karyotype, and only 6 pts (20.7%) had complex karyotype, all of which had AML. Forty-nine pts had 1 PHF6 mutation, and 7 pts had 2 PHF6 mutations. The median variant allelic frequency (VAF) was 10.20% for females and 30.98% for males, with 24 missense, 18 frameshift, 17 nonsense, and 3 splicing mutations identified. Five mutations (8%) occurred in PHD1 and 15 mutations (24%) in PHD2, the 2 zinc finger domains proposed in gene transcription regulation (Figure B). Sequential mutational data was available for 8 pts and revealed an overall increase in PHF6 VAF in 6 pts irrespective of response or therapy. The most commonly co-occurring mutations were those in ASXL1 in 25 pts, RUNX1 and TET2 in 19 pts each, and DNMT3A in 13 pts (Figure C). Response was evaluable in 49 pts. Treatment consisted of hypomethylating agent (HMA) therapy alone in 17 pts (30.4%), HMAs in combination with other therapy in 12 pts (21.4%), intermediate-intensive chemotherapy in 6 pts (10.7%), and high-intensity chemotherapy in 12 pts (21.4%) (Figure D). Overall response rates (ORR) in evaluable pts were 83.3% in treatment-naïve MDS pts who received HMA-based therapy and 100% in those who received chemotherapy; 100% in relapsed/refractory (R/R) MDS pts who received HMA-based therapy; 100% in frontline HMA therapy for CMML pts and 0% in those who received frontline chemotherapy; 100% in R/R CMML pts who received HMA-based treatment; 88.9% in previously untreated AML pts who received HMA-based regimens and 72.7% in therapy-naïve AML pts who received chemotherapy-based regimens; and 66.7% in R/R AML pts who received HMAs and 80.0% in those who received chemotherapy (Figure E). With a median follow-up time of 15.2 months, median overall survival (OS) was not reached for both treatment-naïve and R/R MDS and CMML pts (Figures F and G), 37.0 months for previously untreated AML pts, and not reached for R/R AML pts (Figure H). When compared to newly-diagnosed MDS, CMML, and AML pts with wildtype PHF6 treated during this time period, there was a significant difference in median OS for MDS pts (p=0.001) but no significant differences in median OS for CMML or AML pts. For both treatment-naïve and R/R AML pts, there was no significant median OS difference between HMA-based therapy and chemotherapy-based treatments. Median transformation-free survival was not reached for MDS pts and 20.1 months for CMML pts. Conclusions: PHF6 mutations are relatively uncommon in pts with MDS, CMML, or AML but appear to be associated with normal cytogenetics and mutations in ASXL1, RUNX1, TET2, and DNMT3A. In this small cohort of pts, a statistically significant difference in median OS for MDS pts was observed with no significant differences for CMML or AML pts. Figure Disclosures Sasaki: Otsuka: Honoraria; Pfizer: Consultancy. Alvarado:Jazz Pharmaceuticals: Research Funding; Abbott: Honoraria. Takahashi:Symbio Pharmaceuticals: Consultancy. Kadia:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding; BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Bioline RX: Research Funding. Borthakur:AbbVie: Research Funding; AstraZeneca: Research Funding; Agensys: Research Funding; Xbiotech USA: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Argenx: Membership on an entity's Board of Directors or advisory committees; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Cantargia AB: Research Funding; Merck: Research Funding; Arvinas: Research Funding; Polaris: Research Funding; Strategia Therapeutics: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Eisai: Research Funding; NKarta: Consultancy; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cyclacel: Research Funding; GSK: Research Funding; Janssen: Research Funding; Incyte: Research Funding; Oncoceutics, Inc.: Research Funding; Eli Lilly and Co.: Research Funding; PTC Therapeutics: Consultancy; BMS: Research Funding; Novartis: Research Funding; Bayer Healthcare AG: Research Funding; Oncoceutics: Research Funding. Jabbour:Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding. Kantarjian:Immunogen: Research Funding; Takeda: Honoraria; Pfizer: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Ariad: Research Funding; Daiichi-Sankyo: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Cyclacel: Research Funding; AbbVie: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Jazz Pharma: Research Funding; Astex: Research Funding; BMS: Research Funding. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding.
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Elias, Marjanu Hikmah, Noraziah Nordin, and Nazefah Abdul Hamid. "In Silico Study of Potential Cross-Kingdom Plant MicroRNA Based Regulation in Chronic Myeloid Leukemia." Current Pharmacogenomics and Personalized Medicine 17, no. 2 (October 28, 2020): 125–32. http://dx.doi.org/10.2174/1875692118666200106113610.
Full textAbstract:
Background: Chronic Myeloid Leukaemia (CML) is associated with the BCRABL1 gene, which plays a central role in the pathogenesis of CML. Thus, it is crucial to suppress the expression of BCR-ABL1 in the treatment of CML. MicroRNA is known to be a gene expression regulator and is thus a good candidate for molecularly targeted therapy for CML. Objective: This study aims to identify the microRNAs from edible plants targeting the 3’ Untranslated Region (3’UTR) of BCR-ABL1. Methods: In this in silico analysis, the sequence of 3’UTR of BCR-ABL1 was obtained from Ensembl Genome Browser. PsRNATarget Analysis Server and MicroRNA Target Prediction (miRTar) Server were used to identify miRNAs that have binding conformity with 3’UTR of BCR-ABL1. The MiRBase database was used to validate the species of plants expressing the miRNAs. The RNAfold web server and RNA COMPOSER were used for secondary and tertiary structure prediction, respectively. Results: In silico analyses revealed that cpa-miR8154, csi-miR3952, gma-miR4414-5p, mdm-miR482c, osa-miR1858a and osa-miR1858b show binding conformity with strong molecular interaction towards 3’UTR region of BCR-ABL1. However, only cpa-miR- 8154, osa-miR-1858a and osa-miR-1858b showed good target site accessibility. Conclusion: It is predicted that these microRNAs post-transcriptionally inhibit the BCRABL1 gene and thus could be a potential molecular targeted therapy for CML. However, further studies involving in vitro, in vivo and functional analyses need to be carried out to determine the ability of these miRNAs to form the basis for targeted therapy for CML.
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Marie, JP, R. Zittoun, and BI Sikic. "Multidrug resistance (mdr1) gene expression in adult acute leukemias: correlations with treatment outcome and in vitro drug sensitivity." Blood 78, no. 3 (August 1, 1991): 586–92. http://dx.doi.org/10.1182/blood.v78.3.586.586.
Full textAbstract:
Abstract Resistance to multiple chemotherapeutic agents has been related to the production of P-glycoprotein, a trans-membrane drug efflux pump that is encoded by the multidrug resistance (MDR) gene mdr1. To investigate whether mdr1 could be involved in clinical resistance to chemotherapy in acute leukemias, we have analyzed retrospectively the RNA from adult acute leukemia cells by slot-blot hybridization with a human mdr1 probe. Units of mdr1 expression were defined by reference to drug- sensitive human sarcoma and K562 leukemia cell lines (1 U) and the highly resistant doxorubicin selected leukemia cells K562/R7 (50 U). We studied 41 adult patients with acute leukemias: 5 acute lymphoblastic leukemias, 23 acute myeloid leukemias, and 13 secondary leukemias or blast crisis of chronic myelogenous leukemia. Expression of 10 U or more of mdr1 was found in 6 of 31 (19%) leukemias at diagnosis, versus 5 of 10 (50%) after relapse from therapy, P = .06. The complete remission rate and in vitro sensitivity to daunorubicin were both correlated with low expression (1 U, v 2 U or more) of mdr1. Among 36 evaluable attempts to induce remission, the complete remission rate was 67% (8 of 12) for patients with undetectable or minimal mdr1 expression (1 U), versus 29% (7 of 24) in patients with 2 U or more of expression, P = .03. In vitro resistance to daunorubicin or other MDR-related drugs was associated with expression of 2 U or more of mdr1 in 11 of 11 cases, while specimens that were sensitive to these agents were negative for mdr1 expression in 5 of 11 cases, P = .03. These data suggest that mdr1 expression contributes to chemoresistance in acute leukemia. Determination of mdr1 gene expression may be useful in designing therapy for patients with leukemia.
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Marie, JP, R. Zittoun, and BI Sikic. "Multidrug resistance (mdr1) gene expression in adult acute leukemias: correlations with treatment outcome and in vitro drug sensitivity." Blood 78, no. 3 (August 1, 1991): 586–92. http://dx.doi.org/10.1182/blood.v78.3.586.bloodjournal783586.
Full textAbstract:
Resistance to multiple chemotherapeutic agents has been related to the production of P-glycoprotein, a trans-membrane drug efflux pump that is encoded by the multidrug resistance (MDR) gene mdr1. To investigate whether mdr1 could be involved in clinical resistance to chemotherapy in acute leukemias, we have analyzed retrospectively the RNA from adult acute leukemia cells by slot-blot hybridization with a human mdr1 probe. Units of mdr1 expression were defined by reference to drug- sensitive human sarcoma and K562 leukemia cell lines (1 U) and the highly resistant doxorubicin selected leukemia cells K562/R7 (50 U). We studied 41 adult patients with acute leukemias: 5 acute lymphoblastic leukemias, 23 acute myeloid leukemias, and 13 secondary leukemias or blast crisis of chronic myelogenous leukemia. Expression of 10 U or more of mdr1 was found in 6 of 31 (19%) leukemias at diagnosis, versus 5 of 10 (50%) after relapse from therapy, P = .06. The complete remission rate and in vitro sensitivity to daunorubicin were both correlated with low expression (1 U, v 2 U or more) of mdr1. Among 36 evaluable attempts to induce remission, the complete remission rate was 67% (8 of 12) for patients with undetectable or minimal mdr1 expression (1 U), versus 29% (7 of 24) in patients with 2 U or more of expression, P = .03. In vitro resistance to daunorubicin or other MDR-related drugs was associated with expression of 2 U or more of mdr1 in 11 of 11 cases, while specimens that were sensitive to these agents were negative for mdr1 expression in 5 of 11 cases, P = .03. These data suggest that mdr1 expression contributes to chemoresistance in acute leukemia. Determination of mdr1 gene expression may be useful in designing therapy for patients with leukemia.
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Cilloni, Daniela, Monica Pradotto, Francesca Messa, Francesca Arruga, Enrico Bracco, Sonia Carturan, Chiara Maffè, et al. "Identification of Rab5 as a Gene Involved in Chronic Myeloid Leukemia (CML) Progression." Blood 114, no. 22 (November 20, 2009): 3470. http://dx.doi.org/10.1182/blood.v114.22.3470.3470.
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Abstract Abstract 3470 Poster Board III-358 The role of Bcr-Abl in the pathogenesis of Chronic Myeloid Leukemia (CML) is well established, however, the mechanisms leading to CML progression remain poorly understood. By using our model of transgenic Drosophila Melanogaster (Dm) for human Bcr-Abl driven CML we have identified Rab5 as a gene involved in the regulation of CML progression. The Rab5 is a member of gene family small GTPases which are involved in the regulation of vesicular transport. Lately several important reports have linked some members of the Rab family to invesivness and migration of cancer cells. Rab5 is associate with alpha-integrin subunits and modulates their endosomal traffic and subcellular localization. We have observed that a loss of function of Rab5 gene have induced a worsening of the CML phenotype generated by hBcr-Abl expression. In contrast, Rab gain of function rescued Bcr-Abl phenotype. The aim of the study was to evaluate the expression of Rab5 in CML cells to better understand if a potential correlation with progression, which has been observed in the model, could be confirmed in patients. Methods Rab5 gene expression was measured by Real Time PCR in 90 samples from 80 CML patients (32 PB and 58 BM). Among those, 53 are collected at diagnosis (19 of 53 patients have been enrolled in TOPS study). In addition, 9 samples from in CP patients have been collected at the time of imatinib resistance, 7 in accelerated phase and 11 in BC. In 14 patients, genes expression was analyzed during remission as, well. In parallel, 21 healthy donors (10 PB and 11 BM) have been evaluated. Rab5 protein expression was investigated by Western Blot and Immunofluorescence. We have also utilized K562 transfected with Rab5 plasmid, which we have generated to gain insight about the effects of Rab5 on cell proliferation and apoptosis. Results Rab5 transfection and overexpression in K562 significantly reduced proliferation and affected apoptosis. We found that in CML patients Rab5 expression levels were significantly decreased in either BM or PB (p<0.001 and p<0.0001) as compared to healthy subjects. Furthermore, in blast crisis samples we have found Rab5 transcripts levels to be further decreased. In contrast, at the time of remission, the transcript levels were comparable to normal values. Our preliminary analysis of samples from TOPS trial have shown a trend that Rab5 levels are lower among those patients achieving MMR by 12 months, when compared to the group of patients non achieving MMR on 400 mg, but that difference was not statistically significant (p=0.2). Among those randomized to receive imatinib 800 mg the difference was statistically significant with a median value among those achieving MMR of 1.27 vs 2.14 in the group without MMR (p=0.04). The protein levels have been analyzed by Western Blot and immunofluorescence and allow us to show detectable levels of Rab5 in samples collected at remission, but undetectable levels in course of active CML disease. Although preliminary, our results show a significant decrease of Rab5 expression in blast crisis samples, when compared to CP CML and healthy volunteers, which suggest a role of Rab5 in slowing down or suppressing a progression. Surprisingly, among CP CML patients the responders to TKI therapy have been detected to express a lower level of Rab5 than non responders. We are conducting further studies to better explain these data, which we find intriguing and suggesting that molecular factors involved in the regulation of CML progression could be uncoupled from the mechanisms regulating response to TKI therapy. Supported by Novartis Oncology, Clinical Development, TOPS Clinical Correlative Studies Network Disclosures No relevant conflicts of interest to declare.
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Rinke, Jenny, Andrew Chase, Nicholas C. P. Cross, Andreas Hochhaus, and Thomas Ernst. "EZH2 in Myeloid Malignancies." Cells 9, no. 7 (July 8, 2020): 1639. http://dx.doi.org/10.3390/cells9071639.
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Our understanding of the significance of epigenetic dysregulation in the pathogenesis of myeloid malignancies has greatly advanced in the past decade. Enhancer of Zeste Homolog 2 (EZH2) is the catalytic core component of the Polycomb Repressive Complex 2 (PRC2), which is responsible for gene silencing through trimethylation of H3K27. EZH2 dysregulation is highly tumorigenic and has been observed in various cancers, with EZH2 acting as an oncogene or a tumor-suppressor depending on cellular context. While loss-of-function mutations of EZH2 frequently affect patients with myelodysplastic/myeloproliferative neoplasms, myelodysplastic syndrome and myelofibrosis, cases of chronic myeloid leukemia (CML) seem to be largely characterized by EZH2 overexpression. A variety of other factors frequently aberrant in myeloid leukemia can affect PRC2 function and disease pathogenesis, including Additional Sex Combs Like 1 (ASXL1) and splicing gene mutations. As the genetic background of myeloid malignancies is largely heterogeneous, it is not surprising that EZH2 mutations act in conjunction with other aberrations. Since EZH2 mutations are considered to be early events in disease pathogenesis, they are of therapeutic interest to researchers, though targeting of EZH2 loss-of-function does present unique challenges. Preliminary research indicates that combined tyrosine kinase inhibitor (TKI) and EZH2 inhibitor therapy may provide a strategy to eliminate the residual disease burden in CML to allow patients to remain in treatment-free remission.
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Haslam, Karl, Stephen E. Langabeer, Johanna Kelly, Natasha Coen, Niamh M. O’Connell, and Eibhlin Conneally. "Allogeneic Hematopoietic Stem Cell Transplantation for aBCR-FGFR1Myeloproliferative Neoplasm Presenting as Acute Lymphoblastic Leukemia." Case Reports in Hematology 2012 (2012): 1–5. http://dx.doi.org/10.1155/2012/620967.
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Hematopoietic myeloproliferative neoplasms (MPNS) with rearrangements of the receptor tyrosine kinaseFGFR1gene, located on chromosome 8p11, are uncommon and associated with diverse presentations such as atypical chronic myeloid leukemia, acute myeloid leukemia, or an acute T- or B-lymphoblastic leukemia, reflecting the hematopoietic stem cell origin of the disease. A review of MPN patients with the t(8;22) translocation that results in a chimericBCR-FGFR1fusion gene reveals that this disease either presents or rapidly transforms into an acute leukemia that is generally unresponsive to currently available chemotherapeutic regimens including tyrosine kinase inhibitors (TKIS). The first case of a rareBCR-FGFR1MPN presenting in a B-acute lymphoblastic phase who underwent allogeneic hematopoietic stem cell transplantation (HSCT) with a subsequent sustained complete molecular remission is described. Allogeneic HSCT is currently the only available therapy capable of achieving long-term remission inBCR-FGFR1MPN patients.