Articles de revues : « Pediatric B-Cell Precursor »

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Reid, Gregor S. D., Kevin She, Luke Terrett, Michael R. Food, Jacqueline D. Trudeau et Kirk R. Schultz. « CpG stimulation of precursor B-lineage acute lymphoblastic leukemia induces a distinct change in costimulatory molecule expression and shifts allogeneic T cells toward a Th1 response ». Blood 105, n^o 9 (1 mai 2005) : 3641–47. http://dx.doi.org/10.1182/blood-2004-06-2468.

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AbstractImmunostimulatory DNA containing unmethylated cytosine-phosphate-guanosine (CpG) induces the development of T helper 1 (Th1) immune responses. The response of B cells to CpG stimulation involves increased proliferation, cytokine production, and costimulatory molecule expression. Similar effects have been observed following CpG stimulation of a variety of malignant B cells. Pediatric precursor B acute lymphoblastic leukemia (B-ALL) cells express low levels of costimulatory molecules and are generally poor stimulators of T-cell responses. In this study, we evaluated the impact of CpG stimulation on precursor B-ALL cell lines and pediatric patient-derived samples. The ability to respond to CpG oligodeoxynucleotides was determined by the level of Toll-like receptor 9 (TLR9) expression. In contrast to both nonleukemic B-cell precursors and mature B cells, the response of precursor B-ALL cells was characterized by increased CD40 expression but only small changes in CD86 levels and no induction of CD80 expression. CpG stimulation of ALL blasts produced increased levels of interleukin-6 (IL-6), IL-8, and IL-10 but no detectable IL-12p70 and led to a skewing of allogeneic T cells, with enhanced interferon γ (IFN-γ) production and reduced secretion of IL-5. These results demonstrate the functional relevance of CpG stimulation of precursor B-ALL cells and provide a rational basis for study of these agents for use in treatment of this disease.

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Kroeze, Emma, Laura Arias Padilla, Max Bakker, Judith M. Boer, Melanie M. Hagleitner, Birgit Burkhardt, Takeshi Mori et al. « Pediatric Precursor B-Cell Lymphoblastic Malignancies : From Extramedullary to Medullary Involvement ». Cancers 14, n^o 16 (12 août 2022) : 3895. http://dx.doi.org/10.3390/cancers14163895.

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B-cell lymphoblastic lymphoma (BCP-LBL) and B-cell acute lymphoblastic leukemia (BCP-ALL) are the malignant counterparts of immature B-cells. BCP-ALL is the most common hematological malignancy in childhood, while BCP-LBL accounts for only 1% of all hematological malignancies in children. Therefore, BCP-ALL has been well studied and treatment protocols have changed over the last decades, whereas treatment for BCP-LBL has stayed roughly the same. Clinical characteristics of 364 pediatric patients with precursor B-cell malignancies were studied, consisting of BCP-LBL (n = 210) and BCP-ALL (n = 154) patients. Our results indicate that based on the clinical presentation of disease, B-cell malignancies probably represent a spectrum ranging from complete isolated medullary disease to apparent complete extramedullary disease. Hepatosplenomegaly and peripheral blood involvement are the most important discriminators, as both seen in 80% and 95% of the BCP-ALL patients and in 2% of the BCP-LBL patients, respectively. In addition, we show that the overall survival rates in this cohort differ significantly between BCP-LBL and BCP-ALL patients aged 1–18 years (p = 0.0080), and that the outcome for infants (0–1 years) with BCP-LBL is significantly decreased compared to BCP-LBL patients of all other pediatric ages (p < 0.0001).

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Lilljebjörn, Henrik, et Thoas Fioretos. « New oncogenic subtypes in pediatric B-cell precursor acute lymphoblastic leukemia ». Blood 130, n^o 12 (21 septembre 2017) : 1395–401. http://dx.doi.org/10.1182/blood-2017-05-742643.

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Abstract Until recently, 20% to 30% of pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) could not be classified into any of the established molecular subtypes. Recent molecular studies of such cases have, however, further clarified their mutational spectrum and identified new oncogenic subtypes consisting of cases with DUX4 rearrangements, ETV6-RUNX1–like gene expression, MEF2D rearrangements, and ZNF384 rearrangements. In this review, we describe these new subtypes, which account for up to 50% of previously unclassified pediatric BCP-ALL cases.

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Fazio, Grazia, Clelia Tiziana Storlazzi, Marco Severgnini, Valeria Cazzaniga, Luciana Impera, Giulia Daniele, Ilaria Iacobucci et al. « Novel Chimeric Transcripts Involving PAX5 in B-Cell Precursor ALL ». Blood 122, n^o 21 (15 novembre 2013) : 1367. http://dx.doi.org/10.1182/blood.v122.21.1367.1367.

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Abstract PAX5, located on 9p13, belongs to the PAX gene family and encodes for a transcription factor essential for B lymphoid cell commitment. It functions both as a transcriptional activator and repressor of different target genes involved in lineages development. PAX5 has been recently reported to be target of aberrancies (including point mutation, deletions, and gene fusions), in approximately 30% of pediatric patients affected by BCP-ALL, the most frequent leukemia subset in children. Translocations are estimated to occur at an incidence of 2-3%, with a variety of partner genes, encoding for transcription factors (TEL, PML, FOXP1), kinases (JAK2), structural proteins (ELN, POM121) or molecules of unknown function (C20orf112, AUTS2). We performed a FISH-based study on an Italian cohort of BCP-ALL patients having 9p13 chromosomal rearrangement (as a hallmark of PAX5 rearrangement), and we identified novel PAX5 partner genes. Two pediatric patients were harboring a t(7;9)(q11.2;p13.2) with a PAX5/AUTS2 fusion transcript, thus confirming its recurrent alteration in pediatric B-ALL. Three novel partner genes of PAX5 were identified by FISH. SOX5 was found as a PAX5 partner in a pediatric patient harboring a dic(9;12)(p13;p13) chromosome. A further patient, showing a t(9;12)(p13;q34) translocation, revealed PAX5 as fused to a novel transcript isoform of CHFR, a gene widely expressed in a library of normal tissues. A third partner was identified in an adult B-ALL case, which showed a deletion within the short arm of chromosome 9, leading to the fusion of PAX5 to MLLT3. A fourth PAX-rearranged case, involving POM121C (different from the already described POM121) as fused to PAX5 in a t(7;9)(q11;p13) translocation, was identified by a RNAseq approach on BCP-ALL cases without known prognostic features. The breakpoint on chromosome 7q11 is similar to the one associated with PAX5/AUTS2. An accurate FISH analysis was performed on bone marrow cells of all cases to dissect the genomic breakpoints and the structure of the rearrangements. The fusion genes were cloned by 5’ and/or 3’ RACE PCR, confirmed by sequencing and verified by RT-PCR with specific primers on the source material. PAX5-translocated cases were further characterized by genome-wide Single Nucleotide Polymorphism array. Interestingly, Copy Number Variation analysis showed that a limited number of cooperative genetic lesions were present in addition to the translocation event, thus suggesting a primary role of the PAX rearrangement in leukemogenesis. We therefore hypothesize that PAX5 alterations may represent single genetic aberration events in a simple background, rather than being part of a complex scenario of cooperating genetic lesions involved in leukemogenesis. A common pathway for all PAX5 genomic lesions still need to be elucidated. Disclosures: No relevant conflicts of interest to declare.

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Colomar-Carando, Natalia, Laurent Gauthier, Pietro Merli, Fabrizio Loiacono, Paolo Canevali, Michela Falco, Federica Galaverna et al. « Exploiting Natural Killer Cell Engagers to Control Pediatric B-cell Precursor Acute Lymphoblastic Leukemia ». Cancer Immunology Research 10, n^o 3 (1 mars 2022) : 291–302. http://dx.doi.org/10.1158/2326-6066.cir-21-0843.

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Abstract Natural killer (NK) cells represent a promising cell type in antitumor immunotherapy for efficacy and safety, particularly in the treatment of hematologic malignancies. NK cells have been shown to exert antileukemia activity in the context of haploidentical hematopoietic stem cell transplantation (haplo-HSCT). Products have been developed to boost the activation of NK cells only when cross-linked by tumor cells, avoiding any off-target effect. Here, we tested the in vitro effect of different NK-cell engagers (NKCE), which trigger either NKp46 or NKp30 together with CD16A, and target either CD19 or CD20 to induce killing of pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Target cells were NALM-16 and MHH-CALL-4 cell lines and four primary leukemias, while effector cells were resting NK cells derived from healthy donors and pediatric patients with leukemia after αβT/B-depleted haplo-HSCT. The NK cell–resistant MHH-CALL-4 was efficiently killed using all NKCEs. Boosting of NK activity against MHH-CALL-4 was also evident by degranulation and IFNγ production. Because of the lack of CD20 and high expression of CD19 on primary BCP-ALL, we focused on NKCEs targeting CD19. NKp46- and NKp30-based NKCEs displayed similar potency at inducing NK-cell activity, even when challenged with primary BCP-ALL blasts. Their efficacy was shown also using NK cells derived from transplanted patients. NKCE-induced activation against BCP-ALL can override HLA-specific inhibitory interactions, although the strongest response was observed by the alloreactive NK-cell subset. These data support the therapeutic use of NKp46/CD16A/CD19-NKCE to fight refractory/relapsed leukemia in pretransplantation or posttransplantation settings.

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Borker, A., et N. Chaudhary. « Pediatric precursor B-cell lymphoblastic lymphoma presenting with extensive skeletal lesions ». Annals of Medical and Health Sciences Research 3, n^o 2 (2013) : 262. http://dx.doi.org/10.4103/2141-9248.113673.

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Taneja, Vipul, Goud Raghvendra et Kusum Mahajan. « Association of Acute Lymphoblastic Leukemia with Unilateral Facial Palsy : A Rare Presentation ». International Journal of Health Sciences and Research 11, n^o 8 (6 août 2021) : 79–80. http://dx.doi.org/10.52403/ijhsr.20210811.

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Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer. Survival probability of pediatric ALL had been 10-20%, but the most recent clinical trials with multiagent chemotherapy have achieved overall survival probability of better than 80%. This is achieved because of better supportive care, treatment stratification based on relapse risk, and the biological features of leukemic cells. Diagnosis of ALL was based principally on morphological identification of leukemic blasts in bone marrow, and immunophenotype assessment by flow cytometry is necessary, and most pediatric ALL cases are clinically classified as B-cell precursor, T-cell ALL, or mature B-cell types. Key words: Acute Lymphoblastic Leukemia, ALL, Unilateral Facial palsy, pediatric ALL.

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Dworzak, Michael N., Gerhard Fritsch, Gertraud Fröschl, Dieter Printz et Helmut Gadner. « Four-Color Flow Cytometric Investigation of Terminal Deoxynucleotidyl Transferase–Positive Lymphoid Precursors in Pediatric Bone Marrow : CD79a Expression Precedes CD19 in Early B-Cell Ontogeny ». Blood 92, n^o 9 (1 novembre 1998) : 3203–9. http://dx.doi.org/10.1182/blood.v92.9.3203.

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Abstract Terminal deoxynucleotidyl transferase (TdT)-positive cells in human bone marrow (BM) are a phenotypically inhomogeneous population of precursor cells. In their majority, these TdT+ cells are unambiguously committed to the B lineage, as evidenced by CD19 expression. However, TdT+ precursors that lack CD19 also exist and these may encompass a differentiation potential for the B as well as for other lineages. Because recent data suggested that CD19 expression is not the earliest differentiation event in B-cell ontogeny, we sought to reevaluate TdT+ lymphoid precursors in pediatric BM to define the phenotypic denominator of B-lineage affiliation upstream of CD19. Using four-color flow cytometry, we focused on the assessment of the CD79a antigen, which is highly B-cell specific and which may also be expressed very early in B-cell ontogeny. We found that a majority of TdT+ cells coexpressed CD19 and CD79a in addition to CD10 and CD34, whereas, in all investigated samples, some TdT+ precursors lacked CD19 but expressed CD79a, which suggestively indicates also their B-lineage affiliation. In contrast to the CD19+precursors, which were usually CD10hi and CD79b+, these CD19−CD79a+putative B-cell precursors preferentially expressed CD10 at low levels and were CD79b+ in only 41%. About 17% of these TdT+CD19−CD79a+ precursors also coexpressed CD33 and CD7, but not myeloperoxidase, CD14, or cytoplasmic CD3, which is discussed in the light of cellular activation rather than lineage promiscuity. Our data confirm that the earliest differentiation stages of B cells can be dissected upon expression of the lineage antigens CD79a and CD19 and imply that CD79a is earlier expressed than CD19. This raises the chance to follow the sequential events heralding B-cell commitment in the most immature precursors by correlating phenotypic and genetic differentiation markers. © 1998 by The American Society of Hematology.

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Dworzak, Michael N., Gerhard Fritsch, Gertraud Fröschl, Dieter Printz et Helmut Gadner. « Four-Color Flow Cytometric Investigation of Terminal Deoxynucleotidyl Transferase–Positive Lymphoid Precursors in Pediatric Bone Marrow : CD79a Expression Precedes CD19 in Early B-Cell Ontogeny ». Blood 92, n^o 9 (1 novembre 1998) : 3203–9. http://dx.doi.org/10.1182/blood.v92.9.3203.421k34_3203_3209.

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Terminal deoxynucleotidyl transferase (TdT)-positive cells in human bone marrow (BM) are a phenotypically inhomogeneous population of precursor cells. In their majority, these TdT+ cells are unambiguously committed to the B lineage, as evidenced by CD19 expression. However, TdT+ precursors that lack CD19 also exist and these may encompass a differentiation potential for the B as well as for other lineages. Because recent data suggested that CD19 expression is not the earliest differentiation event in B-cell ontogeny, we sought to reevaluate TdT+ lymphoid precursors in pediatric BM to define the phenotypic denominator of B-lineage affiliation upstream of CD19. Using four-color flow cytometry, we focused on the assessment of the CD79a antigen, which is highly B-cell specific and which may also be expressed very early in B-cell ontogeny. We found that a majority of TdT+ cells coexpressed CD19 and CD79a in addition to CD10 and CD34, whereas, in all investigated samples, some TdT+ precursors lacked CD19 but expressed CD79a, which suggestively indicates also their B-lineage affiliation. In contrast to the CD19+precursors, which were usually CD10hi and CD79b+, these CD19−CD79a+putative B-cell precursors preferentially expressed CD10 at low levels and were CD79b+ in only 41%. About 17% of these TdT+CD19−CD79a+ precursors also coexpressed CD33 and CD7, but not myeloperoxidase, CD14, or cytoplasmic CD3, which is discussed in the light of cellular activation rather than lineage promiscuity. Our data confirm that the earliest differentiation stages of B cells can be dissected upon expression of the lineage antigens CD79a and CD19 and imply that CD79a is earlier expressed than CD19. This raises the chance to follow the sequential events heralding B-cell commitment in the most immature precursors by correlating phenotypic and genetic differentiation markers. © 1998 by The American Society of Hematology.

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Veltroni, Marinella, Maddalena Paganin, Chiara Frasson, Giulia Fabbri, Antonio Marzollo, Elena Seganfreddo, Emanuela Giarin, Elena Fortunato, Maurizio Aricó et Giuseppe Basso. « Clonal Profile Analysis of Leukemic Progenitors and Diagnosis Blast Cells in Pediatric B-Cell Precursor Acute Lymphoblastic Leukemia ». Blood 112, n^o 11 (16 novembre 2008) : 4879. http://dx.doi.org/10.1182/blood.v112.11.4879.4879.

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Abstract Recent studies suggest that the majority of malignant cells found in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) arise from a rare population of leukemic progenitors. Little information is available on the presence of clonal rearrangements in cells at the stage of early precursor. To address this issue we analyzed clonality profile of early leukemic precursors sorted by flow-cytometry. Leukemic cells were obtained from bone marrow samples collected at diagnosis from 6 patients with childhood BCP-ALL. Furthermore, bone marrow cells were collected from 3 healthy children who were harvested for bone marrow donation. Three subpopulations of leukemic cells were investigated: total unsorted blasts, the sorted CD34+/CD38−/CD19+, and the sorted CD34+/CD38−/CD19− cells. Immunoglobulin (Ig) and T-cell receptor (TCR) gene rearrangements were screened by polymerase chain reaction (PCR) in the sorted populations and in the bulk leukemic cells in order to identify molecular markers of clonal evolution. Sequence analysis was then performed on the N-region. Overall, a total of 38 different Ig/TCR gene rearrangements were identified in the 3 cell populations under study (total blasts, CD34+/CD38−/CD19+, and CD34+/CD38−/CD19−). Of them, 13 (34%) were found in the three populations; 12 (31%) were found in two of the three populations: 7 in total blasts and CD19+ subset, 3 in total blasts and CD19−, 2 in CD19− and CD19+; finally, 13 were found only in one subpopulation: 4 in total blast cell, 5 in CD19+, 4 in CD19−. In all the six patients studied, BCP-ALL progenitors CD34+/CD38−/CD19− and CD19+ and the bulk tumor blasts shared at least one Ig/TCR gene clonal rearrangement with the same N-region. In 5 out of 6 patients at least one rearrangement detected in the BCP-ALL progenitors was undetectable in total blasts. Conversely, in 3 patients the clonal rearrangement observed in the bulk leukemic cells was not identified in any of the two sorted ALL precursor populations. Clonal rearrangement was never detected in the samples from healthy bone marrow donors. Our findings confirm that clonal rearrangement may be detected at the stage of early B-lineage precursor CD34+/CD38−/CD19−, suggesting that leukemic transformation may occur at this stage or even before in BCP-ALL. We plan to extend this observation by repopulating studies in NOD/SCID mice.

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Semchenkova, Alexandra, Ekaterina Mikhailova, Alexander Komkov, Marina Gaskova, Ruslan Abasov, Evgenii Matveev, Marat Kazanov et al. « Lineage Conversion in Pediatric B-Cell Precursor Acute Leukemia under Blinatumomab Therapy ». International Journal of Molecular Sciences 23, n^o 7 (5 avril 2022) : 4019. http://dx.doi.org/10.3390/ijms23074019.

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We report incidence and deep molecular characteristics of lineage switch in 182 pediatric patients affected by B-cell precursor acute lymphoblastic leukemia (BCP-ALL), who were treated with blinatumomab. We documented six cases of lineage switch that occurred after or during blinatumomab exposure. Therefore, lineage conversion was found in 17.4% of all resistance cases (4/27) and 3.2% of relapses (2/63). Half of patients switched completely from BCP-ALL to CD19-negative acute myeloid leukemia, others retained CD19-positive B-blasts and acquired an additional CD19-negative blast population: myeloid or unclassifiable. Five patients had KMT2A gene rearrangements; one had TCF3::ZNF384 translocation. The presented cases showed consistency of gene rearrangements and fusion transcripts across initially diagnosed leukemia and lineage switch. In two of six patients, the clonal architecture assessed by IG/TR gene rearrangements was stable, while in others, loss of clones or gain of new clones was noted. KMT2A-r patients demonstrated very few additional mutations, while in the TCF3::ZNF384 case, lineage switch was accompanied by a large set of additional mutations. The immunophenotype of an existing leukemia sometimes changes via different mechanisms and with different additional molecular changes. Careful investigation of all BM compartments together with all molecular –minimal residual disease studies can lead to reliable identification of lineage switch.

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Chaber, Radosław, Artur Gurgul, Jacek Tabarkiewicz, Grażyna Wróbel, Tomasz Szmatoła, Igor Jasielczuk, Olga Haus et al. « MicroRNA gene methylation landscape in pediatric B-cell precursor acute lymphoblastic leukemia ». Advances in Clinical and Experimental Medicine 31, n^o 3 (29 janvier 2022) : 293–305. http://dx.doi.org/10.17219/acem/144170.

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van den Berk, Lieke C. J., Arian van der Veer, Marieke E. Willemse, Myrte J. G. A. Theeuwes, Mirjam W. Luijendijk, Wing H. Tong, Inge M. van der Sluis, Rob Pieters et Monique L. den Boer. « Disturbed CXCR4/CXCL12 Axis In Pediatric Precursor B-Cell Acute Lymphoblastic Leukemia ». Blood 122, n^o 21 (15 novembre 2013) : 2643. http://dx.doi.org/10.1182/blood.v122.21.2643.2643.

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Abstract Malignant cells that infiltrate the bone marrow (BM) interfere with the normal cellular behavior of supporting cells, thereby creating an alternative malignant niche. This intercellular communication is mostly mediated by cytokines and their receptors. In this study, we find that expression of the CXCR4 receptor is significantly increased in pediatric precursor B-cell acute lymphoblastic leukemia (BCP-ALL) cells compared with normal mononuclear hematopoietic cells derived of the bone marrow (p=0.016). Furthermore, we show that high CXCR4 expression is correlated with an unfavorable clinical outcome in BCP-ALL (5-yr CIR ±SE: 38.4% ±6.9% in CXCR4-high versus 12.0% ±4.6% in CXCR4-low expressing patients, p<0.001). Interestingly, BM serum levels of the CXCR4 ligand (CXCL12) are 2.7-fold lower (p=0.005) in samples taken at initial diagnosis of BCP-ALL compared with the levels in samples taken of non-leukemic controls. We show that induction chemotherapy restores CXCL12 levels in the BM to normal levels. Blocking the CXCR4 receptor with Plerixafor (FDA-approved drug) showed that the lower CXCL12 serum levels at initial diagnosis could not be explained by consumption by the leukemic cells, nor did we observe an altered CXCL12-production capacity of BM-MSC at this time-point. We rather observed that a very high density of leukemic cells negatively affected CXCL12 production by the BM-MSC while stimulating the secretion levels of G-CSF. These results suggest that highly proliferative leukemic cells are able to down-regulate the production of cytokines involved in homing (CXCL12), while simultaneously up-regulating the production of cytokines involved in hematopoietic mobilization (G-CSF). This disbalance may stimulate the spreading of BCP-ALL outside the BM. The data presented here suggest that interference with the CXCR4/CXCL12 axis (for instance by using Plerixafor) may be an effective way to mobilize BCP-ALL cells; the more ALL cells become mobilized, the less ALL cells may escape from combination chemotherapy. In proof-of concept studies, this hypothesis needs to be validated to pave the way for implementation in future treatment protocols for children with ALL. Disclosures: No relevant conflicts of interest to declare.

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Szczepanski, Tomasz, Urszula Malek, Lukasz Sedek, Alicja Sonsala, Joanna Zawitkowska, Teresa Odoj, Iwona Malinowska et al. « Heterogeneity Of CXCR4 Expression In Pediatric B-Cell Precursor Acute Lymphoblastic Leukemia ». Blood 122, n^o 21 (15 novembre 2013) : 4652. http://dx.doi.org/10.1182/blood.v122.21.4652.4652.

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Background CXCR4 (CD184) is a receptor specific to the Stromal Derived Factor 1 (SDF-1), a ligand also known as CXCL12. The ligand-receptor interaction has a pleiotropic effect on hematopoietic cell proliferation, migration and activation through several signaling pathways. CXCR4 expression on neoplastic cells might be responsible for their dissemination to particular organs with cells expressing CXCL12 (e.g. lymph nodes, bones, and within bone marrow). In B-cell precursor acute lymphoblastic leukemia (BCP-ALL), expression of CXCR4 was associated with higher capacity of leukemic blasts to seed into bone marrow niches. Aim of the study The study aimed at thorough analysis of CXCR4 expression on BCP-ALL blasts and correlation of CXCR4 expression with the expression of other antigens such as CD66c, CD34, CD10, CD38, CD20 and CD45 as well as with the levels of minimal residual disease on day 15. Patients and methods The study group consisted of 198 consecutive children aged 0-18 years (median 4.4 years) treated for BCP-ALL in the centers of the Polish Pediatric Leukemia/Lymphoma Study Group. Bone marrow samples obtained at initial diagnosis were stained with monoclonal antibodies (CD58, CD66c, CD34, CD19, CD10, CD38, CD20, CD45, CXCR4) in two 8-color tubes and analyzed with multiparameter flow cytometry (BD FACS Canto II, Becton Dickinson, San Jose, CA, USA) according to the EuroFlow standard protocols. The expression of particular antigens on BCP-ALL blasts was defined by median fluorescence. In 177 patients the samples from day 15 were available and analyzed for the presence of minimal residual disease (MRD) with multicolor flow cytometry. Infinicyt software (Cytognos, Salamanca, Spain) was used for more detailed analyses of the flow cytometric data. Results The expression of CXCR4 in BCP-ALL was highly variable with median fluorescence ranging from 252 to 24 388 (median 4011). There was no obvious correlation of CXCR4 expression with immunophenotype and with the expression of other analyzed markers (CD66, CD34, CD10, CD38 i CD45). The only borderline significant correlation found was between CXCR4 and CD20 expression. On day 15, 70 children (39%) demonstrated MRD levels below 0.1%, which is consistent with MRD-based low-risk group. Among these patients, 41 children had undetectable MRD already at this time point. In contrary, MRD levels > 10% were recorded in 21 patients (12%), who were stratified to high-risk group, accordingly. Maximal MRD levels recorded at day 15 were 85.6%. In remaining 86 children (49%), MRD levels at day 15 were in-between 0.1% and 10%, which reflects intermediate response to the treatment. There was no correlation between CXCR4 expression and MRD levels at day 15. Conclusion CXCR4 expression on BCP-ALL blasts is highly heterogeneous and is not associated with particular leukemia immunophenotype. Further analyses should characterize clinical features of leukemia and treatment response with regard to CXCR4 expression. The study was supported by Polish National Center of Science grant N N407 687040. Disclosures: No relevant conflicts of interest to declare.

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Szczepanski, Tomasz, Urszula Malek, Lukasz Sedek, Alicja Sonsala, Joanna Zawitkowska, Teresa Odoj, Iwona Malinowska et al. « Heterogeneity Of CXCR4 Expression In Pediatric B-Cell Precursor Acute Lymphoblastic Leukemia ». Blood 122, n^o 21 (15 novembre 2013) : 4952. http://dx.doi.org/10.1182/blood.v122.21.4952.4952.

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Abstract Background CXCR4 (CD184) is a receptor specific to the Stromal Derived Factor 1 (SDF-1), a ligand also known as CXCL12. The ligand-receptor interaction has a pleiotropic effect on hematopoietic cell proliferation, migration and activation through several signaling pathways. CXCR4 expression on neoplastic cells might be responsible for their dissemination to particular organs with cells expressing CXCL12 (e.g. lymph nodes, bones, and within bone marrow). In B-cell precursor acute lymphoblastic leukemia (BCP-ALL), expression of CXCR4 was associated with higher capacity of leukemic blasts to seed into bone marrow niches. Aim of the study The study aimed at thorough analysis of CXCR4 expression on BCP-ALL blasts and correlation of CXCR4 expression with the expression of other antigens such as CD66c, CD34, CD10, CD38, CD20 and CD45 as well as with the levels of minimal residual disease on day 15. Patients and Methods The study group consisted of 198 consecutive children aged 0-18 years (median 4.4 years) treated for BCP-ALL in the centers of the Polish Pediatric Leukemia/Lymphoma Study Group. Bone marrow samples obtained at initial diagnosis were stained with monoclonal antibodies (CD58, CD66c, CD34, CD19, CD10, CD38, CD20, CD45, CXCR4) in two 8-color tubes and analyzed with multiparameter flow cytometry (BD FACSCanto II, Becton Dickinson, San Jose, CA, USA) according to the EuroFlow standard protocols. The expression of particular antigens on BCP-ALL blasts was defined by median fluorescence. In 177 patients the samples from day 15 were available and analyzed for the presence of minimal residual disease (MRD) with multicolor flow cytometry. Infinicyt software (Cytognos, Salamanca, Spain) was used for more detailed analyses of the flow cytometric data. Results The expression of CXCR4 in BCP-ALL was highly variable with median fluorescence ranging from 252 to 24 388 (median 4011). There was no obvious correlation of CXCR4 expression with immunophenotype and with the expression of other analyzed markers (CD66, CD34, CD10, CD38 i CD45). The only borderline significant correlation found was between CXCR4 and CD20 expression. On day 15, 70 children (39%) demonstrated MRD levels below 0.1%, which is consistent with MRD-based low-risk group. Among these patients, 41 children had undetectable MRD already at this time point. In contrary, MRD levels > 10% were recorded in 21 patients (12%), who were stratified to high-risk group, accordingly. Maximal MRD levels recorded at day 15 were 85.6%. In remaining 86 children (49%), MRD levels at day 15 were in-between 0.1% and 10%, which reflects intermediate response to the treatment. There was no correlation between CXCR4 expression and MRD levels at day 15. Conclusion CXCR4 expression on BCP-ALL blasts is highly heterogeneous and is not associated with particular leukemia immunophenotype. Further analyses should characterize clinical features of leukemia and treatment response with regard to CXCR4 expression. The study was supported by Polish National Center of Science grant N N407 687040. Disclosures: No relevant conflicts of interest to declare.

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Pathak, Nivedita, Rachna Seth et Akhilesh Mishra. « Expression of B lymphocyte antigen in pediatric B-cell precursor acute lymphoblastic leukemia : AIIMS Experience ». Pediatric Hematology Oncology Journal 1, n^o 2 (2016) : S9. http://dx.doi.org/10.1016/j.phoj.2016.10.024.

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Steeghs, Elisabeth M. P., Isabel S. Jerchel, Willemieke de Goffau-Nobel, Alex Q. Hoogkamer, Judith M. Boer, Aurélie Boeree, Cesca van de Ven et al. « JAK2 Aberrations in Childhood B-Cell Precursor Acute Lymphoblastic Leukemia ». Blood 128, n^o 22 (2 décembre 2016) : 583. http://dx.doi.org/10.1182/blood.v128.22.583.583.

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Abstract Background In high risk pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) patients, gain of function mutations and translocations affecting JAK2 have been described. These mutations and translocations result in aberrant kinase signaling and may therefore serve as an ideal target for precision medicines. Aim Evaluate the frequency and prognosis of JAK2 lesions among different subtypes of childhood BCP-ALL, and study the efficacy of the JAK1/2 inhibitors momelotinib and ruxolitinib. Methods This study comprised 77 BCR-ABL1-like cases and 76 B-other cases which were screened for JAK2 translocations using RT-PCR. Furthermore a representative pediatric cohort of 461 newly diagnosed BCP-ALL cases was screened for JAK2 mutations using targeted next-generation sequencing. Clinical analyses were performed in 341 BCP-ALL patients. Patient-derived-xenograft (PDX) cells were isolated from NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) mice, which were injected with primary leukemic cells. Purity of PDX cells was enriched to over 90% and presence or absence of JAK2 lesions was validated. PDX and primary leukemic cells were exposed to a dilution series of momelotinib or ruxolitinib for four days. Where indicated, cells were pre-incubated with 25 ng/ml TSLP for 1 hour. In mono-culture assays, cytotoxicity was quantified using MTT and in co-culture assays flow cytometry was used. Leukemic cells were discriminated from mesenchymal stromal cells (MSCs) using CD19 and viability was assessed by Annexin V and Propidium Iodide. Western blotting was used to study protein expression levels. Results JAK2 translocations were detected in 6.5% of BCR-ABL1-like cases (3 PAX5-JAK2 cases, 1 TERF2-JAK2 case and 1 BCR-JAK2 case), but not in B-other cases. JAK2 mutations were identified in 3.5% of all BCP-ALL cases, which included JAK2 mutations in BCR-ABL1-like (7.6%), B-other (11.9%), and high hyperdiploid cases (1.6%), but not in MLL rearranged, BCR-ABL1-positive, ETV6-RUNX1-positive or TCF3-PBX1-positive cases. Cumulative incidence of relapse in patients harboring JAK2 lesions was as poor as in JAK2 wildtype BCR-ABL1-like and B-other patients. Efficacy of the JAK1/2 inhibitors momelotinib and ruxolitinib was examined in JAK2 lesion positive (primary and PDX) leukemic cells. Inhibitors were cytotoxic in both translocated and mutated cells, although efficacy in JAK2 mutated cells highly depended on CRLF2 activation by TSLP. CRLF2 activation resulted in downstream STAT5 activation and sensitization towards ruxolitinib compared to unstimulated cells (p < 0.05). Cells harboring JAK2 translocations signaled independently of CRLF2. Although momelotinib and ruxolitinib exposure blocked downstream STAT1/5 phosphorylation, both inhibitors also induced accumulation of phosphorylated JAK2Y1007. Consequently, release of the inhibitors resulted in a profound re-activation of JAK2 signaling, observed by upregulation of downstream STAT1/5 signaling. Furthermore, we observed microenvironment-induced resistance. Culturing leukemic cells in the presence of primary bone marrow MSCs induced resistance to ruxolitinib, compared to leukemic cells in single cultures (p < 0.05). A similar trend was observed for momelotinib. In addition, patients harboring JAK2 mutations displayed a heterogeneous leukemic cell population. Mouse xenograft models revealed different outgrowth patterns of leukemic cells, in which the JAK2 mutated clone persisted, decreased or even disappeared, resulting in outgrowth of JAK2 wildtype leukemic cells. Moreover, JAK2 mutations were not mutually exclusive for other pathway mutations (e.g. KRAS). Conclusion JAK2 translocations and mutations were detected in poor prognostic BCP-ALL cases. In ex vivo assays, the JAK1/2 inhibitors momelotinib and ruxolitinib were cytotoxic in JAK2 aberrant cells. Despite these promising findings, we identified certain limitations of these inhibitors. Inhibitors induced accumulation of phosphorylated JAK2Y1007, which resulted in a profound re-activation of JAK2 signaling upon their release. Furthermore, our data suggest that the effect of JAK inhibition may be compromised by mutations in alternative survival pathways and by microenvironment-induced resistance. Taken together, our data yield important directives for the clinical use of JAK inhibitors in pediatric BCP-ALL. Disclosures No relevant conflicts of interest to declare.

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Troeger, A., M. Siepermann, G. Escherich, R. Meisel, R. Willers, S. Gudowius, T. Moritz et al. « Survivin and its prognostic significance in pediatric acute B-cell precursor lymphoblastic leukemia ». Haematologica 92, n^o 8 (1 août 2007) : 1043–50. http://dx.doi.org/10.3324/haematol.10675.

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Liu, Zhimou, Xu Yang, Jie Liu et Jigang Yang. « FDG PET/CT Demonstrated Precursor B-cell Lymphoblastic Lymphoma in a Pediatric Patient With Hemophilia B ». Clinical Nuclear Medicine 44, n^o 8 (août 2019) : 683–85. http://dx.doi.org/10.1097/rlu.0000000000002582.

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Waanders, Esmee, Frank N. van Leeuwen, Eugene Verwiel, Simon V. van Reijmersdal, Marloes R. Levers, Joost C. van Galen, Edwin Sonneveld, Peter M. Hoogerbrugge, Ad Geurts van Kessel et Roland P. Kuiper. « Pediatric Precursor-B ALL with BTG1 Deletions Show a Distinct Genomic Profile. » Blood 114, n^o 22 (20 novembre 2009) : 3244. http://dx.doi.org/10.1182/blood.v114.22.3244.3244.

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Abstract Abstract 3244 Poster Board III-181 Recent genome-wide profiling studies have revealed that childhood acute lymphoblastic leukemia (ALL) is characterized by recurrent microdeletions, including the cell cycle regulator CDKN2A, the B-cell differentiation genes PAX5, EBF1 and IKZF1 (Ikaros) and the anti-proliferative gene B-cell translocation gene 1 (BTG1). In a previous study, we have shown that BTG1 is an important determinant of glucocorticoid sensitivity (Van Galen et al. Blood/ ASH Annual Meeting Abstracts, 2008). In the present study we have characterized these cases in more detail and elucidated the frequency of recurrent lesions in BTG1 deletion cases. Using locus-specific MLPA screening of an unselected cohort of 305 precursor B-ALL cases, we identified 26 microdeletions (8.5%). All deletions encompassed BTG1 only. We were able to genomically profile 22 diagnosis samples using Affimetrix SNP6.0 arrays. Of these, 12 did not develop a relapse during a minimal of 4,5 years of follow up. The mean number of CNVs was 29.6 of which 10.3 gains and 22.5 losses (median size 512 kb and 115 kb respectively). BTG1 deletions were generally focal, varying in size from 104 kb to 1,4 Mb. In all but one patient the breakpoints at the 5' end of the deletion tightly clustered and subsequent fine-mapping using qPCR revealed that this breakpoint cluster was located within intron 1 of the BTG1 gene. At the 3'end of the deletion, four breakpoint clusters could be identified. Analysis of the copy number variation (CNV) profiles showed that patients with a BTG1 deletion more often harbored a deletion in IKZF1 compared to an unselected cohort of pre-B ALL cases (27% vs 7%, chi-square p=0.042). In contrast, recurrent CNVs like PAX5, EBF1 and CDKN2A/B occur in similar frequencies (23%, 9% and 32% vs 17%, 0% and 23% respectively). In addition, the BTG1 deletion cases that developed into a relapse showed significantly more often a deletion in CDKN2A/B compared to the BTG1 deletion cases that did not develop a relapse (60% vs 8%, p=0.02). Together, these data indicate that pediatric precursor-B ALL carrying BTG1 deletions have distinct genomic profiles, showing increased frequencies of deletions in IKZF1 and CDKN2A. Disclosures No relevant conflicts of interest to declare.

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Dulau Florea, Alina E., Raul C. Braylan, Kristian T. Schafernak, Stefania Pittaluga, Steven M. Holland, Gulbu Uzel et Katherine R. Calvo. « Abnormal B-Cell Maturation Pattern in the Bone Marrow of Patients with Germline Mutations in PIK3CD ». Blood 124, n^o 21 (6 décembre 2014) : 2752. http://dx.doi.org/10.1182/blood.v124.21.2752.2752.

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Abstract Background Autosomal dominant germline mutations in the phosphatidylinositol-3-OH kinase (PIK3CD) encoding for the PI(3)K catalytic subunit p110δ, lead to combined immunodeficiency with increased incidence of B-cell lymphomas. (Lucas CL et.al. Nature Immunology 2014). While p110δ is selectively expressed in leukocytes, it is critical for TCR and BCR signaling and lymphocyte homeostasis. Clinically, these patients may present with sinopulmonary infections, bronchiectasis, cytomegalovirus (CMV) and/or Epstein-Barr virus (EBV) viremia, lymphoproliferation and autoimmune cytopenias. Immune phenotype includes naïve CD4+ T cell lymphopenia, expanded terminally differentiated or exhausted T cells, increased circulating transitional B cells and reduced class-switched memory B cells. Herein we report immunophenotypic abnormalities in B-lymphoid maturation in the bone marrow (BM) of 5 patients with PIK3CD mutations. Methods BM from 5 patients with PIK3CD mutations (2 males, 3 females, age range: 4–15 years, median 11.5 years) were studied by flow cytometry (FC), morphology and immunohistochemistry (IHC). BM aspirate from 5 healthy age matched pediatric patients were used as controls for flow cytometric analysis of B-cell subsets and maturation. Antibodies against CD45, CD3, CD4, CD8, CD19, CD10, CD34, CD20, and surface kappa and lambda light chains were used for FC. B-lymphocyte subsets were defined as: early stage precursor B-cells (CD34+/CD19+/CD10+bright/CD20-); intermediate precursor B-cells (CD45+moderate/ CD19+/CD10+moderate/CD34-); and late stage and mature B cells (CD34-/CD10-/CD19+/CD45+bright/CD20+). The intermediate subset corresponds to transitional B cells (developmentally intermediate between immature and mature naive B cells). IHC and in situ hybridization staining were applied to biopsy sections using standard methods. Prism software was used for statistical analyses (Mann-Whitney test). Results There was no significant difference in the median percentage of early B-cell precursors (among all B-lymphocytes) between the PIK3CD patients and the age-matched controls (3.6% vs. 3.7%; p=0.8). However, all PIK3CD marrows showed expanded CD10+ intermediate precursor B-cells which were overall 2.5 times more abundant in PIK3CD marrows than in controls (94.6% vs. 37.4% of all B-cells; p<0.01). Additionally, the PIK3CD patients showed a marked reduction in mature B-cells with 29 times fewer mature CD20+/CD10- B-cells than controls (2% vs 57%; p<0.01). These differences resulted in a markedly abnormal B-cell maturation pattern in all PIK3CD patients (Figs. A and B). A subset of CD10+ and bright CD20+ B-cells expressed polytypic light chains in the PIK3CD marrows. The median CD4:CD8 T-cell ratio was 0.32 in PIK3CD marrows with markedly reduced CD4+ T-cells. BM core biopsies showed overall normal cellularity with increased lymphocytes (20-30% of the cellular marrow). IHC revealed increased CD20+ lymphocytes (15-20% of all nucleated cells) and CD10+ lymphocytes showed similar distribution suggesting coexpression with CD20. TdT and CD34 highlighted approximately 5% of all nucleated cells. CD138, and kappa and lambda light chains showed unremarkable scattered polytypic plasma cells. CD3+ and CD8+ T-cells accounted for 5-10% of BM cells and CD4+ lymphocytes were reduced. EBV was positive in one case. CMV was negative in all cases. Conclusions For the first time, we report B-cell maturation abnormalities in the bone marrow of patients with germline mutations in PIK3CD. All marrows showed an abnormal pattern of B cell maturation characterized by an absolute increase in CD10+ intermediate precursor B-cells and a marked decrease in mature B-cells. The findings suggest either a partial block in B-cell late stage maturation or other mechanism leading to increased CD10+ B-cell precursors and markedly reduced mature B-cells. Lymphoid hyperplasia and lymphoma have been described in PIK3CD patients. The increased CD10+ B cell precursors and the abnormal maturation pattern noted by flow cytometry may mimic CD10+ B-cell neoplasia (e.g. acute lymphoblastic leukemia or Burkitt lymphoma) but detailed analysis showed no morphologic or immunophenotypic evidence of B-cell neoplastic involvement in any of the five patients studied. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Maury, Sébastien, Françoise Huguet, Arnaud Pigneux, Emmanuel Raffoux, Xavier Thomas, Kheira Beldjord, Eric Delabesse et al. « Prognostic Significance of CD20 Expression in Adult B-Cell Precursor Acute Lymphoblastic Leukemia. » Blood 110, n^o 11 (16 novembre 2007) : 2829. http://dx.doi.org/10.1182/blood.v110.11.2829.2829.

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Abstract Introduction: CD20 expression is classically considered to be associated with inferior survival in adults with B-cell precursor acute lymphoblastic leukemia (ALL) but this notion is not strongly sustained in the literature. A recent pediatric study performed at St Jude’s Children’s Research Hospital reports that CD20 expression does not appear to be associated with inferior outcome in a cohort of 359 patients treated with contemporary regimens. This question is of importance notably since favorable experience has been reported for the use of rituximab, a chimeric monoclonal antibody to CD20, in combination with chemotherapy in mature B-cell lymphoma and leukemia, and possibly also in adult B-cell precursor ALL. Method: To determine the prognostic impact of CD20 expression in adult patients with B-cell precursor ALL and therefore the potential utility of rituximab in this subset of patients, we studied 143 patients treated in the GRAALL-2003 trial, designed to offer a dose-intensive pediatric-like approach in adults with Ph-negative ALL until 55 years of age. Results: CD20 positivity, defined as expression of CD20 in more than 20% of leukemia blasts, was observed in 49 patients (34%). There was no association between CD20 expression and patient age, white blood cell count at diagnosis, E2A-PBX, or ploidy. None of 21 patients with MLL-AF4 expressed CD20 (p<0.001). Even if CD20 expression tended to be associated with corticoresistance (24% in CD20+ cases vs. 14% in others, p=0.16), it was not associated with chemoresistance, overall early response (cortico- and/or chemoresistant ALL), CR rate, or post-induction MRD >10-3, as assessed by clonal Ig rearrangements quantification. However, the cumulative incidence of relapse at 30 months was significantly higher in CD20+ cases (39% [95% CI, 25 to 55] vs. 20% [95% CI, 13 to 31], p=0.02). Interestingly, a negative impact of corticoresistance and high white blood cell count at diagnosis on the cumulative incidence of relapse was only observed in this population of CD20+ patients (p=0.05 and p<0.001, respectively), but not in CD20neg patients (p=0.85 and 0.67). These data suggest either an intrinsic resistance of CD20+ leukemic cells or a lack of impact on these cells of the dose intensification (reinforcement of the induction course with a sequential bolus administration of cyclophosphamide) applied to corticoresistant patients. Disease-free survivals at 30 months were of 57% [95% CI, 40 to 70] and 64% [95% CI, 52 to 74] in CD20+ and CD20neg groups, respectively (p=0.36). Conclusion: In contrast to pediatric ALL, CD20 expression appears to be associated with inferior outcome in adult ALL with a significantly higher cumulative incidence of relapse in this group of patients. This reinforces the interest of evaluating the effect of rituximab combined to chemotherapy in adult ALL.

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Wilson, Bridget S., Xiangbing Meng, Tomas Mazel, Cheryl L. Willman, Susan Atlas, Richard Harvey, I.-Ming Chen, Stephen P. Hunger, Janet M. Oliver et Stuart S. Winter. « Select γ-Secretase Inhibitors Induce Apoptosis in Pre-B ALL Cells and Disrupt the Balance Between Constitutive Notch Signaling and Repression. » Blood 112, n^o 11 (16 novembre 2008) : 1917. http://dx.doi.org/10.1182/blood.v112.11.1917.1917.

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Abstract Several γ secretase inhibitors (GSIs) were tested for the ability to induce apoptosis in precursor B acute lymphoblastic leukemia (pre-B ALL) cells. Of five GSI’s tested, treatment with two compounds resulted in effective killing of both pre-B lymphoblasts and cells from multiple pre-B ALL lines. Since Notch receptors represent an important group of γ secretase targets, we evaluated expression and activation status of Notch receptors in CD19+ lymphoblasts from pediatric pre-B ALL patients, as well as cultured pre-B ALL cells. We found that, unlike T-ALL where activating mutations are common, pre-B ALL cells appear to drive constitutive Notch signaling through autocrine signals. Blasts from 11 patients expressed 3 Notch receptors and multiple Notch counter-ligands. Expression of Notch pathway genes was also confirmed by microarray analysis of genes expressed in 207 children with high risk B precursor ALL. GSI treatment of pre-B ALL cells led to dephosphorylation of AKT and Foxo3, Bim expression and caspase activation. GSI treatment also blocked cleavage of Notch 1 and 2 to their active forms and inhibited expression of Notch targets, Hey2 and Myc. In contrast, increased expression of Hes1 and Hey1 was correlated with GSI-induced loss of the co-repressor, SMRT. GSI treatment appears to induce precursor B cell death by disrupting the balance between constitutive Notch signaling and repression.

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Bornhauser, Beat, Gunnar Cario, Anna Rinaldi, Thomas Risch, Virginia Rodriguez Martinez, Moritz Schütte, Hans-Jörg Warnatz et al. « The hematopoietic stem cell marker VNN2 is associated with chemoresistance in pediatric B-cell precursor ALL ». Blood Advances 4, n^o 17 (27 août 2020) : 4052–64. http://dx.doi.org/10.1182/bloodadvances.2019000938.

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Abstract Most relapses of acute lymphoblastic leukemia (ALL) occur in patients with a medium risk (MR) for relapse on the Associazione Italiana di Ematologia e Oncologia Pediatrica and Berlin-Frankfurt-Münster (AIEOP-BFM) ALL protocol, based on persistence of minimal residual disease (MRD). New insights into biological features that are associated with MRD are needed. Here, we identify the glycosylphosphatidylinositol-anchored cell surface protein vanin-2 (VNN2; GPI-80) by charting the cell surface proteome of MRD very high-risk (HR) B-cell precursor (BCP) ALL using a chemoproteomics strategy. The correlation between VNN2 transcript and surface protein expression enabled a retrospective analysis (ALL-BFM 2000; N = 770 cases) using quantitative polymerase chain reaction to confirm the association of VNN2 with MRD and independent prediction of worse outcome. Using flow cytometry, we detected VNN2 expression in 2 waves, in human adult bone marrow stem and progenitor cells and in the mature myeloid compartment, in line with proposed roles for fetal hematopoietic stem cells and inflammation. Prospective validation by flow cytometry in the ongoing clinical trial (AIEOP-BFM 2009) identified 10% (103/1069) of VNN2+ BCP ALL patients at first diagnosis, primarily in the MRD MR (48/103, 47%) and HR (37/103, 36%) groups, across various cytogenetic subtypes. We also detected frequent mutations in epigenetic regulators in VNN2+ ALLs, including histone H3 methyltransferases MLL2, SETD2, and EZH2 and demethylase KDM6A. Inactivation of the VNN2 gene did not impair leukemia repopulation capacity in xenografts. Taken together, VNN2 marks a cellular state of increased resistance to chemotherapy that warrants further investigations. Therefore, this marker should be included in diagnostic flow cytometry panels.

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Jiang, Chuang, Jiabi Qian, Wenge Hao, Wei LIU, Shuhong Shen, Hua Jiang et Hui Zhang. « Novel MEIS1-FOXO1 Fusion Gene in a Case of Pediatric B-Cell Precursor Acute Lymphoblastic Leukemia ». Blood 132, Supplement 1 (29 novembre 2018) : 5283. http://dx.doi.org/10.1182/blood-2018-99-116354.

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Abstract Background: Thanks to the total therapy and systemic basic-translation research, the overall survival rate in children with acute lymphoblastic leukemia (ALL) has dramatically improved to almost 90% over these past few decades. FOXO1 gene belongs to the forkhead family of transcription factors, which play roles in myogenic growth and differentiation. Translocation of FOXO1 with PAX3 has been reported in pediatric alveolar rhabdomyosarcoma. In B-cell precursor ALL, two cases with FOXO1 fusions have been identified already, while its function on ALL remains unknown. Here, we report a novel MEIS1-FOXO1 fusion gene in a case with B-ALL. Methods: Flowcytometery, karyotype, RT-PCR and fluorescence in were employed, MEIS1-FOXO1 was identified as novel fusion gene in a case of pediatric BCP-ALL. Using IL-3 dependent BaF3 cells as study model to test the leukemia transformation potential of MEIS1-FOXO1. Results: A novel MEIS1-FOXO1 fusion was identified in one cease of pediatric B-ALL. Panel next generation sequencing (NGS) showed that the leukemia clone had concurrent NRASG12D, TP53R273H, WHSC1E1099K, ABCC1R1166X, PHGR1H37P, HOXA3P219L and DSTP4606L somatic mutation. This patient was enrolled in CCCG-ALL2015 clinical trial (ChiCTR-IPR-14005706) and achieved completed remission and low minimal residual disease (MRD) level (MRD<0.01%) at day 19 from induction therapy. Functional study showed that MEIS1-FOXO1 fusion gene can potentiate BaF3 cells growth independent of IL3 supplement, as compared to those without MEIS1-FOXO1 fusion transduction. In the meanwhile, we have found that MEIS1-FOXO1 fusion gene can drive cells into S-phase with concurrent decreased G0/G1 phase, which might be its oncogenic role in leukemogenesis. Using qPCR methods, we have found that MEIS1-FOXO1 fusion gene altered the cell cycle related genes expression. Conclusions: Integrating the FOXO1-fusion reports, our data have added more evidence to underline the role of FOXO1 deregulation in the pathogenesis of acute lymphoblastic leukemia. Novel fusion of MEIS1-FOXO1 can potentiate B-ALL via cell cycle entry. Detailed mechanisms involved into the MEIS1-FOXO1 should be further investigated. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

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Xu, Jason, Changya Chen, Tiffaney Vincent, Elizabeth Li, Yusha Sun, Chia-hui Chen, David Frank, David T. Teachey et Kai Tan. « Reference Mapping Pediatric Leukemia Using Single Cell Multiomic Atlas of Pediatric Hematopoiesis ». Blood 138, Supplement 1 (5 novembre 2021) : 3265. http://dx.doi.org/10.1182/blood-2021-153428.

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Abstract Acute lymphoblastic leukemia is the most common pediatric cancer and leading cause of cancer related mortality in pediatric populations. A key challenge to bridge better therapies to patients that fail conventional therapy are to understand their tumor landscape and aberrations in cell signaling, particularly in relation to normal hematopoietic development. To address this gap, we produced a unified reference map of pediatric T, B, and myeloid cell development from the HSPC using single cell RNA-seq and single-cell ATAC-seq on healthy pediatric bone marrow and thymus. We employed 6 different FACS sorting strategies in order to capture rare, but informative, progenitor cell states, including those of the CCR9+ CD34+ CD1A- CD4- CD8- early-T-cell precursor, CD34+ CD1A- CD4- CD8- pro-T cell, and CD34+ CD1A+ CD4- CD8- pre-T cell and Lin-CD34+CD38- multipotent, lymphoid, and myeloid progenitors from the bone marrow. We mapped leukemic cells from patients from 4 different subtypes of pediatric leukemia (T-ALL, ETP-ALL, MPAL, AML) to our healthy reference and found that our reference map can distinguish between subtle differences in transcriptome and epigenome that were undetectable using surface marker or canonical gene expression. Notably, using trajectories inferred from our healthy reference map, we discovered a large amount of inter-tumoral and intra-tumoral heterogeneity, with leukemic blasts from different patients and different populations within any one patient projecting to different cell states along normal development. Finally, we mapped engrafted leukemic cells from patient derived xenografts (PDX) back to our healthy reference. While we observed patient-specific transcriptomic shifts in engrafted versus primary leukemic blasts, we found that the overall transcriptomic hierarchy is maintained in the most PDX, with engrafted cells projecting to near-identical stages of arrest along our healthy hematopoietic trajectory. Interestingly, for PDX that projected to different areas in development compared to primary sample, we discovered alterations in expression of key transcription factors that regulate hematopoietic development. Our single cell multi-omic reference map of pediatric hematopoiesis serves as a valuable reference for mapping RNA-seq and ATAC-seq data back to nearest healthy precursors in normal hematopoietic development. On-going analysis is utilizing single cell transcriptomic, chromatin accessibility data from additional leukemic patients, including patients with B-ALL, to determined key genes and regulators that are altered in comparison to nearest healthy cell-types. In addition, population level signatures learned from healthy reference are being tested in bulk-transcriptomic ALL datasets. We are eager to present the results of these analyses at ASH. *CC and JX, as well as, DTT and KT contributed equally to this work Figure 1 Figure 1. Disclosures Teachey: Janssen: Consultancy; NeoImmune Tech: Research Funding; Sobi: Consultancy; BEAM Therapeutics: Consultancy, Research Funding.

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Schroeder, Michael P., Martin Neumann, Cornelia Eckert, Lorenz Bastian, Alva Rani James, Nicola Gökbuget, Cornelia Schlee et al. « Multi-Genomics of Relapsed B-Cell Precursor Acute Lymphoblastic Leukemia Reveals Three Distinct Genetic Clusters Characterized By Different Alterations ». Blood 128, n^o 22 (2 décembre 2016) : 453. http://dx.doi.org/10.1182/blood.v128.22.453.453.

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Abstract Introduction: Despite the recent identification of the Ph-like subgroup of B-cell precursor Acute Lymphoblastic Leukemia (BCP-ALL), a large number of BCP-ALL patients lack cytogenetic and molecular defined lesions. To get a higher resolution and a broader molecular view of relapsed BCP-ALL, we designed a multi-omics study to reveal age-overriding relapse-driving alterations that may unravel novel molecular targets. Methods: We studied 150 paired samples (initial diagnosis: ID; relapse: REL; complete remission: CR) from 50 patients without known translocations. The cohort consisted of 24 adult and 26 pediatric patients with minimal residual disease < 0.05 % at CR. All patients were treated in population based German study trials (GMALL, BFM). We examined the mutational and copy number status via exome sequencing, obtained expression profiles and fusion-genes via RNA-sequencing and the methylation status via Illumina Methylation Array. Results: With a lenient approach detecting drivers and passengers, we identified significantly more mutations in REL compared to ID samples (adult median: 52 vs 38; pediatric median: 39 vs 27). In addition, we detected 4 hypermutators (more than 100 mutations per sample), 2 were pediatric and 2 were adult samples, 3 of which were REL samples. The most recurrently mutated genes were KRAS (n=15), NRAS (n=15), TP53 (n=13), CDC27 (n=13), KMT2D (n=11), IKZF1 (n=11), CREBBP (n=10) and FLT3 (n=6; Figure 1), with mutations present in both age cohorts. NT5C2, SYK and CHD1 were exclusively mutated in the pediatric cohort with at least 3 mutations. NT5C2 was also specific for early REL. Of all REL mutations, 225 mutations (14%, mean: 4 mutations/patient) were sub-clonal (under < 5% mutation frequency) at ID. Copy number alterations (CNA) varied greatly among pediatric and adult samples: 6% of pediatric and 18% of adult samples had aneuploidies and or copy neutral loss of heterozygosity of whole chromosomes. Chromosomal aberrations at ID persisted at relapse (100 %). Particular targets of CNA affected well-described genes like CDKN2A, CDKN2B, PAX5 on chr9p. Genes preferentially subjected to homozygous deletions were VPREB1 (n=6), SH2B3 (n=4), and ETV6 (n=2). All SH3B2 deletions were found in pediatric samples. On the epi-genomic level, the principal component analysis of the most variable CG-sites revealed a stable methylation profile during the course of the disease. However, we found a clear separation into a smaller pediatric-dominated cluster (n=24; 20 pediatric, 4 adult) and a larger mixed-age cluster (n=76; Fig. 1, Cluster A). Differentially methylated regions, affecting a total of 269 genes, characterized the separation of the smaller cluster, henceforth called Methylation Deregulated (MDR) cluster. The samples of the MDR cluster showed also a distinct gene expression profile by RNA-seq supporting a tight connection between the methylation status and its transcriptional program. A subset of 97 genes was differentially expressed including MAPK and PDGFR genes as most prominently deregulated. Additionally we defined a MDR expression classifier comprising 30 genes (Fig. 1). On the mutational level, the MDR samples had 20 % fewer mutations (mean: 25.3) compared to the remaining samples (mean: 31.3) and fewer CNVs for the most frequently affected genes. Characterising the non-MDR samples, a third of those were categorized as Ph-like ALL using the 15 gene classifier in an unsupervised clustering; this signature also coincided with the presence of well-known fusion-genes (Fig. 1, Cluster B). The remaining samples were defined by chromosomal instability (CI; Fig. 1, Cluster C). In the CI cluster, mutations in epigenetic regulators were twice as frequent when compared to the remaining samples. Conclusions: We describe three distinct clusters in relapsed BCP-ALL, which are characterized by a different genetic alterations: a novel MDR cluster by distinct methylation changes, the Ph-like cluster by gene fusions and the CI cluster by chromosomal instability. The cluster assignment was stable over the course of the disease. All clusters occurred in pediatric and adult patients, with the methylation-driven cluster predominantly in pediatrics. The MDR cluster showed significantly fewer mutations and CNVs compared to the other two clusters. The MDR samples showed activation of the MAPK signaling pathway pointing to actionable therapeutic targets. Figure 1 Figure 1. Disclosures Gökbuget: Pfizer: Honoraria, Research Funding; Amgen: Honoraria, Research Funding.

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Serbanica, Andreea Nicoleta, Delia Codruta Popa, Constantin Caruntu, Sergiu Pasca, Cristian Scheau, Ionut Vlad Serbanica, Raluca Suciu et al. « The Significance of CD20 Intensity Variance in Pediatric Patients with B-Cell Precursor Acute Lymphoblastic Leukemia ». Journal of Clinical Medicine 12, n^o 4 (11 février 2023) : 1451. http://dx.doi.org/10.3390/jcm12041451.

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B-cell precursor acute lyphoblastic leukemia (ALL) is a common pediatric malignancy and patients may have significant benefits from monoclonal antibodies therapy with increased survival rates. Positive CD20 expression is identified in about half of these patients and its presence may serve as a prognostic factor in disease evolution. We performed a retrospective study including 114 patients diagnosed with B-ALL and evaluated the expression of CD20 through flow cytometry at diagnosis and on day 15. Additional immunophenotypic analyses as well as cytogenetic and molecular genetic analyses were also performed. We observed an increase in the mean fluorescence intensity (MFI) of CD20 between diagnosis—1.9 (1.2–3.26) and day 15: 6.17 (2.14–27.4), (p < 0.0001). Furthermore, we assessed that both diagnosis and day 15 CD20 MFI had an impact on RFS and OS, respectively, for cut-off values of >8.08 at diagnosis and >28.65 at day 15. In conclusion, CD20 expression appears to be a poor prognostic feature of B-ALL in pediatric patients. In this study, stratification of the outcome by the intensity of CD20 has implications concerning the allocation to rituximab-based chemotherapy and may offer new, potentially useful information for pediatric patients with B-ALL.

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Kogner, P., A. Ericsson, G. Barbany, H. Persson, E. Theodorsson et O. Bjork. « Neuropeptide Y (NPY) synthesis in lymphoblasts and increased plasma NPY in pediatric B-cell precursor leukemia ». Blood 80, n^o 5 (1 septembre 1992) : 1324–29. http://dx.doi.org/10.1182/blood.v80.5.1324.1324.

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Abstract Neuropeptide Y (NPY), a regulatory peptide in both the central and peripheral nervous systems, has recently been found in neuroendocrine tumors as well as in the bone marrow of rat and certain autoimmune mice, but not in human bone marrow. To investigate a possible role for NPY in the human hematopoietic system, we have prospectively studied NPY-like immunoreactivity in plasma (P-NPY-LI) and NPY mRNA in bone marrow from children with acute leukemia. Northern blot showed high levels of NPY mRNA in bone marrow and peripheral lymphoblasts from children with B-cell precursor leukemia. In situ hybridization showed NPY mRNA in malignant B-cell precursor lymphoblasts. No NPY mRNA was detected in the bone marrow of children with T-cell leukemia. P-NPY-LI was higher (P less than .001) in 51 children with leukemia (200:50 to 385 pmol/L, median:interquartile range) compared to 51 age-matched healthy controls (37:20 to 52 pmol/L). P-NPY-LI was higher (P less than .001) in those with favorable clinical risk classification. Elevated P- NPY-LI, compared with the upper age-adjusted reference limit, was only found in children with B-cell precursor leukemia (31 of 40), whereas all children with B-cell, T-cell, or myeloid leukemia (n = 11) had normal P-NPY-LI (P less than .001). During the 2- to 46-month follow- up, children with elevated P-NPY-LI had better (P less than .001) outcome compared to those with normal P-NPY-LI (79.4% v 34.6% probability for event-free survival).

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Kogner, P., A. Ericsson, G. Barbany, H. Persson, E. Theodorsson et O. Bjork. « Neuropeptide Y (NPY) synthesis in lymphoblasts and increased plasma NPY in pediatric B-cell precursor leukemia ». Blood 80, n^o 5 (1 septembre 1992) : 1324–29. http://dx.doi.org/10.1182/blood.v80.5.1324.bloodjournal8051324.

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Neuropeptide Y (NPY), a regulatory peptide in both the central and peripheral nervous systems, has recently been found in neuroendocrine tumors as well as in the bone marrow of rat and certain autoimmune mice, but not in human bone marrow. To investigate a possible role for NPY in the human hematopoietic system, we have prospectively studied NPY-like immunoreactivity in plasma (P-NPY-LI) and NPY mRNA in bone marrow from children with acute leukemia. Northern blot showed high levels of NPY mRNA in bone marrow and peripheral lymphoblasts from children with B-cell precursor leukemia. In situ hybridization showed NPY mRNA in malignant B-cell precursor lymphoblasts. No NPY mRNA was detected in the bone marrow of children with T-cell leukemia. P-NPY-LI was higher (P less than .001) in 51 children with leukemia (200:50 to 385 pmol/L, median:interquartile range) compared to 51 age-matched healthy controls (37:20 to 52 pmol/L). P-NPY-LI was higher (P less than .001) in those with favorable clinical risk classification. Elevated P- NPY-LI, compared with the upper age-adjusted reference limit, was only found in children with B-cell precursor leukemia (31 of 40), whereas all children with B-cell, T-cell, or myeloid leukemia (n = 11) had normal P-NPY-LI (P less than .001). During the 2- to 46-month follow- up, children with elevated P-NPY-LI had better (P less than .001) outcome compared to those with normal P-NPY-LI (79.4% v 34.6% probability for event-free survival).

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Morisot, Sebastien, Richard Hildreth, Ian M. Kaplan, Maryalice Stetler-Stevenson, Julie A. Taylor, Yachna Ahuja, Lauren Bloom, Alan S. Wayne et Curt I. Civin. « Sensitive NOD-scid-IL2γnull (NOG-scid) Assay for Human Precursor B Acute Lymphoblastic Leukemias (ALL). » Blood 110, n^o 11 (16 novembre 2007) : 4286. http://dx.doi.org/10.1182/blood.v110.11.4286.4286.

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Abstract Results of treatment for childhood ALL have improved considerably over the past few decades, yet still ∼20% of pediatric patients relapse. New in vivo models of human ALL might increase understanding of ALL biology and speed preclinical development of novel treatment regimens. Multiple strains of immunodeficient mice support growth of human ALL cells (Bachmann, Current Drugs Target 2007, review). The recently described highly immunodeficient NOD-scid-IL2γnull (NOG-scid) mouse strain offers a number of advantages over the widely-used NOD-scid strain: NOG-scid mice have a normal lifespan, do not develop spontaneous lymphomas, and require ∼10-fold fewer normal human hematopoietic stem-progenitor cells to generate human hematopoiesis (Hiramatsu, Blood 2003; Ishikawa, Blood 2005). In addition, NOG-scid mice support generation of human leukemia from transplanted human acute myeloid leukemia (AML) (Ninomiya, Leukemia 2007). Herein we report a sensitive in vivo model using transplant of human childhood precursor B ALL cells into sublethally irradiated NOG-scid mice. Transplanted mice developed fatal leukemia 4–5 weeks after intravenous injection of 5x104 REH or KOPN8 cells (established precursor B ALL cell lines derived from pediatric ALL patients). At necropsy, the mice had massive splenomegaly and hyperplastic bone marrow. Blood, spleen, and marrow contained abundant human cells with immunophenotype matching the transplanted ALL cell line. We went on to similarly transplant primary leukemic blast cells from pediatric ALL patients. In 3 of 5 tested primary ALL cases, fatal human leukemias developed in the NOG-scid mice. In titrations of 103-2.5x106 transplanted ALL cells, time to clinical leukemia was dose-dependent, and 1000 primary human cells was sufficient to initiate leukemia development. In addition, we detected human leukemic blast cells by flow cytometric immunophenotyping in the blood of transplanted NOG-scid mice as early as 10 days post-transplant, enabling objective leukemia diagnosis ∼4 weeks prior to clinical signs. CONCLUSIONS: NOG-scid mice supported the generation of human precursor B ALL from cell lines and primary ALL cases, objectively detectable as early as 10 days post-transplant. Our dose titration results suggest that this model detects a high frequency of ALL-initiating cells. This in vivo model may provide a powerful assay both for fundamental questions regarding the biology of leukemia stem cells and for preclinical studies of novel anti-neoplastic agents and regimens.

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Messinger, Yoav H., Paul S. Gaynon, Richard Sposto, Jeannette van der Giessen, Elena Eckroth, Jemily Malvar et Bruce C. Bostrom. « Bortezomib with chemotherapy is highly active in advanced B-precursor acute lymphoblastic leukemia : Therapeutic Advances in Childhood Leukemia & ; Lymphoma (TACL) Study ». Blood 120, n^o 2 (12 juillet 2012) : 285–90. http://dx.doi.org/10.1182/blood-2012-04-418640.

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Abstract Therapy of relapsed pediatric acute lymphoblastic leukemia (ALL) is hampered by low remission rates and high toxicity, especially in second and subsequent relapses. Our phase 1 study, T2005-003, showed that the combination of bortezomib with vincristine, dexamethasone, pegylated asparaginase, and doxorubicin had acceptable toxicity. We report the phase 2 expansion of this combination in patients with relapsed ALL who failed 2-3 previous regimens. Twenty-two patients with relapsed ALL were treated with bortezomib combined with this regimen; their ages ranged from 1 to 22 years, and they had either B-precursor ALL (n = 20) or T-cell ALL (n = 2). Grade 3 peripheral neuropathy developed in 2 (9%) patients. After 3 patients died from bacterial infections, treatment with vancomycin, levofloxacin, and voriconazole prophylaxis resulted in no further infectious mortality in the last 6 patients. Fourteen patients achieved complete remission (CR), and 2 achieved CR without platelet recovery, for an overall 73% response rate, meeting predefined criteria allowing for early closure. B-precursor patients faired best, with 16 of 20 (80%) CR + CR without platelet recovery, whereas the 2 patients with T-cell ALL did not respond. Thus, this combination of bortezomib with chemotherapy is active in B-precursor ALL, and prophylactic antibiotics may be useful in reducing mortality. Bortezomib merits further evaluation in combination therapy in pediatric B-precursor ALL. This study is registered at http://www.clinicaltrials.gov as NCT00440726.

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Tsaur, G. A., A. Е. Druy, A. G. Solodonikov, A. M. Popov, A. P. Shapochnik, L. V. Vakhonina, А. А. Vlasova et al. « IKZF1 DELETIONS ARE INDEPENDENT PROGNOSTIC FACTOR IN PEDIATRIC B-CELL PRECURSOR ACUTE LYMPHOBLASTIC LEUKEMIA ». Oncohematology 11, n^o 4 (1 janvier 2016) : 32–48. http://dx.doi.org/10.17650/1818-8346-2016-11-4-32-48.

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Özdemir, Nihal, Başak Koç, Ezgi P. Uysalol, Cengiz Bayram, Işik O. Al, Rengin Şiraneci, Gülçin Yeğen et Ahmet Salduz. « A Rare Case of Pediatric Bone Precursor B-Cell Lymphoma Presenting With Multiple Fractures ». Journal of Pediatric Hematology/Oncology 40, n^o 6 (août 2018) : 489–90. http://dx.doi.org/10.1097/mph.0000000000001147.

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Yano, Mio, Toshihiko Imamura, Kenichi Sakamoto, Daisuke Asai, Gen Kano, Hajime Hosoi, Takao Deguchi et al. « Clinical Significance of LNK (SH2B3) Expression in Pediatric B Cell Precursor Acute Lymphoblastic Leukemia ». Blood 124, n^o 21 (6 décembre 2014) : 3772. http://dx.doi.org/10.1182/blood.v124.21.3772.3772.

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Abstract Background: In pediatric B cell precursor acute lymphoblastic leukemia (BCP-ALL), aberrant JAK-STAT signaling is one of the key leukemogenic mechanisms. Although activating mutations of JAK2 are found in high-risk BCP-ALL patients in western countries, such mutations are rare in Japanese cohorts, led to speculation of other factors contributing abnormal activation of JAK-STAT pathway. The adaptor protein LNK (SH2B3) is one of the negative regulator of JAK-STAT signaling, and its loss of function mutations have been identified in myeloproliferative neoplasms and high-risk BCP-ALL. In addition, the loss of function of LNK has been demonstrated to increase proliferation of B cells in vivo. Based on these findings, we conducted genetic analysis to determine the prognostic impact of LNKin BCP-ALL, and functional analysis to investigate its possible mechanisms. Methods: For genetic analysis, we evaluated diagnostic bone marrow or peripheral blood samples of 164 pediatric BCP-ALL patients treated with the Japan Association of Childhood Leukemia Study (JACLS) ALL02 protocol along with peripheral blood samples from 9 healthy volunteers. The LNK expression level was determined by qRT-PCR. Deletion of IKZF1 was determined by MLPA, and direct sequencing was employed to detect LNK mutations in patients with IKZF1 deletion. For functional analysis, thrombopoietin (TPO)-dependent BaF3-MPL cells expressing LNK (BaF3-MPL-LNK) was established by retroviral transduction to investigate if LNKexpression levels impact on drug sensitivity for prednisolone (PSL), doxorubicin (DOX) or vincristine (VCR). For growth assay, BaF3-MPL cells with or without LNK were cultured for four days in the presence of TPO and the viable cell number was counted. For drug sensitivity test, BaF3-MPL cells with or without LNK were treated with each drug for 48 hours in the presence of TPO, then the IC50 was calculated. Phospho-specific flow cytometory (Phos-Flow) was performed to measure JAK-STAT activation. Results: The LNK expression levels in pediatric BCP-ALL patients’ samples were significantly lower than in samples from healthy donors (P < 0.01). When analyzing all 164 cases, the expression level of LNK was decreased in relapsed patients but there was no statistical significance (P = 0.067). IKZF1 deletion was found in 25 (15% of all) patients, and in these patients, LNK expression level dose not relate to relapse (P = 0.39). Intriguingly, when patients with known high-risk factor (i.e., IKZF1 deletion or poor response to PSL) were excluded, the expression level of LNK was significantly higher in non-relapsed patients (P < 0.05). In functional assay, we observed inhibition of TPO dependent growth of BaF3-MPL cells by expression of LNK (P < 0.01), consistent with previous reports. Phos-Flow analysis revealed that LNK expression suppressed TPO–induced phosphorylation of STAT5 in BaF3-MPL cells. In drug sensitivity test, we found that IC50 of PSL and DOX were substantially lower in BaF3-MPL-LNK cells from in BaF3-MPL-mock cells (0.70 vs 3.93 nM, P < 0.01 and 0.61 vs 1.14 nM, P < 0.05, respectively). Decline in IC50 of VCR by LNK expression was not statistically significant (1.38 vs 2.45 nM, P = 0.056). We next compared the impact of LNK with Ruxolitinib (RUX), a potent synthesized JAK2 inhibitor. The diminution in IC50 of PSL in BaF3-MPL-mock cells treated with RUX (50 nM) was comparable of that in BaF3-MPL-LNK cells (0.31 nM, combination index (CI) = 0.39), consistent with our hypothesis that LNK is working as a JAK2 inhibitor. Since we identified two amino-acid substitutions in N-terminal proline-rich dimerization domain (R139H) and PH domain (P242S), we also examined their function. Transductions of these genes in BaF3-MPL cells, however, did not alter cell growth, suggesting they are single nucleotide variants. Discussions: Our findings that high LNK expression is associated with low relapse rate in intermediate risk (IKZF1 intact, good PSL response) patients indicate potential of LNK to restrain relapse in such patients, presumably by suppressing JAK-STAT signaling. Since we proved the impact of LNK expression to improve sensitivity of PSL in vitro which was comparable to RUX, RUX could compensate lack of internal LNK expression to induce cell death of BCP-ALL cells. Collectively, targeting JAK-STAT pathway will be promising therapeutic option for intermediate risk BCP-ALL patients with low expression level of LNK. Disclosures No relevant conflicts of interest to declare.

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Zhang, Chuer, et Gladstone Austin Amos Burke. « Pediatric precursor B-cell acute lymphoblastic leukemia with MYC 8q24 translocation – how to treat ? » Leukemia & ; Lymphoma 59, n^o 8 (12 octobre 2017) : 1807–13. http://dx.doi.org/10.1080/10428194.2017.1387914.

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Suppipat, Koramit, Xiao Zhu, Chun Shik Park et H. Daniel Lacorazza. « Anti-Leukemic Property of Sulphoraphane In Precursor B Cell Acute Lymphoblastic Leukemia ». Blood 116, n^o 21 (19 novembre 2010) : 3974. http://dx.doi.org/10.1182/blood.v116.21.3974.3974.

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Abstract Abstract 3974 Acute lymphoblastic leukemia (ALL) is the most common form of hematologic malignancy in children. In spite of significant advances achieved in the treatment of childhood ALL, one fifth of these patients still relapse after the standard treatment. Moreover, relapse ALL is the second most common cause of cancer-related deaths in children. The development of novel therapies is prevented by a limited understanding of the exact pathobiology. There are emerging evidences that the transcription factor KLF4 has a tumor suppressor property in ALL. Recently, a gene expression classifier study in pediatric precursor B-cell ALL (pre-B ALL) showed that KLF4 expression was significantly reduced in high risk ALL patients with positive MRD after induction. This finding suggests a possible role of this cell cycle inhibitor on the development, expansion and drug-resistant of leukemic cells. Several studies demonstrate that overexpression of KLF4 in normal B cells and BCR transformed B cells show increased apoptosis and reduced proliferation. Furthermore, we recently described that KLF4 inhibits proliferation of naïve lymphocytes by activating p21 (Yamada, et al, 2009). Sulphoraphane (SF; 4-methylsulfonylbutyl isothiocyanate) is a dietary compound derived from Cruciferae vegetables with anti-carcinogenic activity in colon cancer by upregulating KLF4 and p21 among other genes. Thus, we hypothesized that SF could also exhibit anti-leukemic activity in human-derived acute lymphoblastic leukemia cells via the activation of KLF4. The pre-B ALL cell lines (Nalm6, REH, RS-4, SUP-B15) and an EBV transformed B cell line were treated with different concentrations of SF (0-40 μM) for 24–48 hours. Then, cell number was estimated using an ATP-based viability method. Flow cytometric analysis of ANNEXIN-V/7-AAD binding as well as CFSE dilution was used to measure apoptosis and proliferation respectively. We found that SF induced cytotoxicity in Nalm-6, REH and RS-4 cell lines in a dose and time dependent manner. This cytotoxic effect was less pronounced in EBV-transformed B cell line. SF treatment led to increased ANNEXIN-V and 7-AAD positive cells (82% apoptotic cells in SF-treated versus 9% in DMSO control). Further, SF-treated cells displayed significantly less proliferation in comparison to DMSO controls thus suggesting that SF inhibits cellular proliferation. Preliminary data also suggest that SF-mediated apoptosis is caused by upregulation of KLF4. In conclusion, Sulphoraphane exhibits an anti-leukemic property by inducing apoptosis and abrogating proliferation in pre-B ALL cell lines. Thus, sulphoraphane could potentially be used as an adjunctive therapy in a subgroup of pre-B ALL patients who have decreased expression of KLF4. Disclosures: No relevant conflicts of interest to declare.

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Schwab, Claire, Sarra L. Ryan, Lucy Chilton, Alannah Elliott, James Murray, Stacey Richardson, Christopher Wragg et al. « EBF1-PDGFRB fusion in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) : genetic profile and clinical implications ». Blood 127, n^o 18 (5 mai 2016) : 2214–18. http://dx.doi.org/10.1182/blood-2015-09-670166.

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Key Points EBF1-PDGFRB fusion accounts for ∼0.5% of B-cell precursor acute lymphoblastic leukemia and 2.7% of the B-other subtype. EBF1-PDGFRB-positive patients are MRD positive and are slow early responders who respond to imatinib.

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Jain, Hasmukh, Manju Sengar, Vasu Babu Goli, Jayashree Thorat, Prashant Tembhare, Dhanlaxmi Shetty, V. N. Avinash Bonda et al. « Bortezomib and rituximab in de novo adolescent/adult CD20-positive, Ph-negative pre-B-cell acute lymphoblastic leukemia ». Blood Advances 5, n^o 17 (30 août 2021) : 3436–44. http://dx.doi.org/10.1182/bloodadvances.2020003368.

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Abstract The expression of CD20 in precursor B-cell acute lymphoblastic leukemia (B-ALL) is associated with poor outcomes. The addition of rituximab to intensive chemotherapy in CD20+ ALL has led to improved outcomes in several studies. However, there is no clear evidence regarding the optimal number of doses and its benefit without an allogeneic stem cell transplant. Achieving measurable residual disease (MRD)-negative status postinduction would reduce the requirement for a transplant. Novel approaches are needed to induce a higher proportion of MRD-negative complete remission in patients with high-risk ALL. Given bortezomib’s activity in relapsed ALL and its synergism with rituximab in B-cell lymphomas, the addition of bortezomib to rituximab and chemotherapy may provide an incremental benefit in CD20+ precursor B-ALL. We conducted a phase 2 study to test the activity of bortezomib and rituximab in combination with a pediatric-inspired regimen during induction therapy in newly diagnosed adolescents and adults (aged >14 years) with CD20+, Philadelphia-negative precursor B-ALL; bone marrow MRD negativity at the end of induction was the primary end point. From December 2017 through August 2019, a total of 35 patients were enrolled. End-of-induction MRD-negative status was achieved in 70.9% of patients, as opposed to 51.7% in the historical cohort treated with chemotherapy alone. MRD-negative rates improved to 87.5% post-consolidation. At a median follow-up of 21 months, event-free survival and overall survival rates were 78.8% (95% confidence interval, 66-94) and 78.7% (95% confidence interval, 65.8-94), respectively. There was no significant increase in toxicity with bortezomib and rituximab compared with the historical cohort. The incidence of neuropathy was 26% (all less than grade 3). The combination of bortezomib, rituximab, and a pediatric-inspired ALL regimen was active and well tolerated in de novo CD20+ Philadelphia-negative precursor B-ALL. This trial was registered with the Clinical Trials Registry-India as CTRI/2017/04/008393(http://ctri.nic.in/Clinicaltrials).

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Glukhanyuk, E. V., A. V. Stepanov, A. M. Popov et M. A. Maschan. « CD-19-directed immunotherapy resistance mechanisms of B-precursor acute lymphoblastic leukemia ». Oncohematology 13, n^o 4 (3 janvier 2019) : 27–36. http://dx.doi.org/10.17650/1818-8346-2019-13-4-27-36.

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Immunotherapy is the most rapidly evolving field in clinical malignant hematology. Targeting of the B-lineage surface antigen CD19 in B-lineage acute lymphoblastic leukemia and B-cell lymphoma is a story of great success. Recently two approaches of CD19 immunotargeting were approved for clinical application: CD3 × CD19 bi-specific T-cell engager blinatumomab and CD19 chimeric antigen receptor (CAR) Tcells. Both approaches demonstrated an unprecedented activity in a cohort of patients with relapsed and refractory B-cell leukemia and lymphoma both in the adult and pediatric population. Early clinical research has showed that tumors are able to escape the immunological control and become resistant to the immune attack. Mechanisms of the tumor immune escape are being actively studied and include diverse pathways, such as alternative splicing of CD19 and immunosuppressive tumor microenvironment. Current review briefly summarizes data regarding the mechanisms of CD19-positive leukemia resistance to CD19 immune targeting and discusses potential approaches to overcome it.

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Davis, Kara L., Erin F. Simonds, Sean C. Bendall, Wendy J. Fantl et Garry P. Nolan. « Mass Cytometry Organizes the Heterogeneity of Pediatric B Cell Acute Lymphoblastic Leukemia ». Blood 118, n^o 21 (18 novembre 2011) : 753. http://dx.doi.org/10.1182/blood.v118.21.753.753.

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Abstract Abstract 753 Pediatric B Cell Acute Lymphoblastic Leukemia: Common and Unique Differentiation States Defined by Signaling Response States Background: When mutations or regulatory dysfunction drive inappropriate cell division or survival this sets the stage for cancer initiation or progression. At what point do cells in an early cancer veer from their normal cellular routines to no longer participate in the development of a normal cellular tissue architecture & differentiation heirarchy? Do they still attempt to play out their programming to some degree, or are they “free actors”? The fact that cancers of any given type appear to remain tied to phenotypic classification schemes is illustrated in traditional clinical stratification systems. Paradoxically, cancers are considered (by some) as “heterogeneous”, whereas as a class they appear to recapitulate patterns of clinical responses, gene expression, signaling states. To what extent are these repeated molecular patterns mirrored at the level of differentiation? We mapped, at the single cell level, patterns of expression of markers and phenotypic traits that might be similar or unique across patient subgroups of pediatric B-cell ALL samples using 35 parameter proteomic mass cytometry. Using the features assignable to each single cell, with a statistical reconstruction of most likely similarity of features in 35 dimensional space, we mapped a “common” differentiation tree previously unrecognized by conventional analyses, and demonstrate here how differences in certain markers distinguish, or create, common phenotypic co-expression features across these ALL patients, or suggest patient-specific derailing of differentiation associated with changes in signaling module expression states. Methods: Cryopreserved cells were obtained from 8 pediatric B cell ALL patients under informed consent. 19 surface markers were used to cluster data into metacells of localized similarity displayed in a tree of local relationships via hierarchical cell lineage clustering and spanning-tree progression analysis of density-normalized events (SPADE) (Figure 1) (Bendall et al, Science 6 May2011; 332: 687–696). Results: The blast cell subpopulations comprised the areas of greatest density on the spanning trees–consistent with the fact that these cells are the most prevalent. Blast populations displayed variable expression of B cell precursor surface markers such as CD10, CD19, CD34 and CD38—even though clinical phenotyping placed all patients in a similar class. SPADE analysis detailed unexpected sub-branches prominently observed in certain patients, while absent or weakly represented in others. This confirms common signaling and differentiation states can be observed across patients, but individual patients can manifest unique and prevalent outgrowths of these common malignant differentiation states. Three patients' disease appears to gain a transformative event during a common point at a “pre-B cell development state, leading to local expansion at this halted population of characteristic immunophenotype. Sample ALL04 appears to have an outgrowth of cells with the earliest pre-B cell progenitors, whereas ALL01 is consistent with a maturing pre B cell, gaining expression of CD45. Notably, ALL03, characterized by an MLL rearrangement, clusters with myeloid cells and is CD10 negative, suggesting transformation prior to lymphocyte commitment. The cellular responses to perturbation provides added structure to the cellular subsets; responses to stimulation of the preB cell receptor are present within the majority of blast populations for ALL01 but absent in most for ALL03 and ALL04. We will present this and other findings related to these patients, as well as application of this approach to other tumor types. Conclusion:This high-dimensional immunophenotypic analysis of single cells from primary patient samples reveals an unseen developmental structure within pediatric B precursor acute lymphoblastic leukemia. The developmental stage at which the transformative event occurs informs the characteristic response to perturbation and critically, to drug treatment. *KD and ES contributed equally to this work. Disclosures: Fantl: Nodality, Inc.: Equity Ownership.

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Rayburg, Melissa S., Daniel Marmer, Jun Mo, Richard McMasters, Teresa Smolarek, Beatrice Lampkin et John Perentesis. « Prevalence and Clinical Characterization of CD20 and CD22 Expression in Pediatric Precursor B-Cell Acute Lymphoblastic Leukemia ». Blood 112, n^o 11 (16 novembre 2008) : 4872. http://dx.doi.org/10.1182/blood.v112.11.4872.4872.

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Abstract Immunophenotypic classification of leukemia has important therapeutic and prognostic implications. In B-cell malignancies, CD20 and CD22 also represent therapeutic targets. CD20 expression in adult patients with B lineage ALL has been associated with a poor prognosis. The data are conflicting in the pediatric population and may be impacted by the type of therapy employed. A recent study of pediatric patients treated in consecutive St Jude Children’s Research Hospital Total Therapy ALL regimens observed excellent outcomes and no prognostic significance for CD20 expression (Jeha et al. Blood2006, 108:3302–3304). We retrospectively analyzed 50 consecutive patients aged 4 months to 28 years with precursor-B ALL treated with contemporary risk-adapted BFM-based ALL regimens for whom flow cytometric, genetic, and early response data were available. Cases were defined as positive for CD20 and/or CD22 expression if surface expression was identified in more than 20% of leukemic blasts. We found that CD22 was expressed at high levels (68–99%) in all patients evaluated. CD20 expression was positive in 27 (54%) of patients. CD20 expression did not correlate with known NCI prognostic features, including presenting white blood count or age. All 3 patients with BCR-ABL translocation ALL were CD20 positive. Consistent with previously published data, neither of the 2 patients with MLL-AF4 translocation were CD20 positive. There was no association of CD20 expression with trisomy 4/10/17 or TEL-AML1 status. We did not observe an association between CD20 expression and rapid early bone marrow response to therapy at day 8 or 15; 47/50 patients were in remission at day 29. At a median follow-up time of 48 months 46/50 patients were alive without relapse. These limited data do not suggest a strong association between CD20 expression and known prognostic features or early treatment response in pediatric precursor-B ALL treated with contemporary BFM therapy platforms. However, our findings of frequent expression of CD22 on precursor-B ALL blasts from children supports its consideration as a target for immunotherapy approaches in high risk or relapsed disease.

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Theunissen, Prisca, Ester Mejstrikova, Tomasz Szczepanski, Lukasz Sedek, Alita van der Sluijs, Alberto Orfao, Jacques JM van Dongen et Vincent H. J. van der Velden. « Recovery of the Normal B-Cell Compartment in Children Treated for B-Cell Precursor Acute Lymphoblastic Leukemia ». Blood 124, n^o 21 (6 décembre 2014) : 3792. http://dx.doi.org/10.1182/blood.v124.21.3792.3792.

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Abstract BACKGROUND Cytotoxic treatment in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) patients induces a dramatic decrease in B-cell precursor (BCP) and mature B-cell numbers, followed by regeneration of BCPs in the bone marrow (BM) and subsequent replenishment of mature B-cells in the peripheral blood (PB) in between treatment blocks and after stop of treatment. To understand the degree of B-cell recovery after such dramatic changes, we first evaluated the composition of the B-cell population in the BM and PB of pediatric BCP-ALL patients during and after therapy. Secondly, we investigated whether the immunophenotypic maturation of BCPs in regenerating BM is similar to normal BCP development or whether such regeneration induces immunophenotypic aberrancies, which could potentially hamper minimal residual disease (MRD) detection. Finally, we assessed whether compensatory proliferation plays a role during B-cell regeneration, since enhanced proliferation might limit the B-cell receptor diversity and consequently may affect susceptibility to infections during and after therapy. METHODS For immunophenotypic characterization of different B-cell subsets, 8-color flow cytometry was performed on fresh BM and PB samples at different time points after start of therapy (DCOG ALL11-protocol). To study BCP maturation, a multidimensional maturation pathway based on 5 backbone markers was designed and the expression pattern of several differentiation markers during this maturation pathway was evaluated. To assess proliferation in BCP subsets, BM samples were stained with subset-specific antibodies and DRAQ5 for cell cycle analysis. The proliferation history of sorted pre-B-II-small and immature subsets in BM and sorted mature B-cell subsets in PB was assessed by performing a kappa-deleting recombination excision circle (KREC)-assay. RESULTS BCP regeneration occurred mainly at day 78, month 5 and after stop of therapy. The BCP compartment in regenerating BM at time points during therapy showed a shift towards the most immature stages. In PB, mature B-cell numbers decreased after start of therapy and newly generated mature B-cells subsets reappeared at month 5 and after stop of therapy. Importantly, the BCP maturation pathway with its expression patterns of CD10, CD34, CD58, CD66c, CD38, CD123, CD9, CD81, CD24, TdT, Igκ and Igλ was comparable between regenerating BM and BM of healthy individuals, albeit that a shift in the relative BCP subset distribution was observed in regenerating BM. As expected, most proliferation in BM of healthy controls occurred in the pre-B-II-large subset (68% ±11% (mean ±SD) proliferating cells). Comparable percentages of proliferating pre-B-II-large cells were found in regenerating BM: 74%±10% at day 78, 72%±10% at month 5 and 63% (preliminary data, n=1) at one year after stop of therapy (month 36). Also pre-B-I cells showed some proliferation, with no significant differences between normal and regenerating BM (Figure 1). If present, the pre-B-II-small and immature BCP subsets showed no proliferation in regenerating and normal BM. KREC-analysis of sorted pre-B-II-small and immature subsets confirmed that no cell divisions had occurred after IGK-rearrangement in normal BM as well as regenerating BM at month 5 and month 36. Low numbers of pre-B-II-small and immature cells precluded KREC-analysis at day 78. KREC-analysis of the various mature B-cell subsets in PB showed no significant difference in proliferation history between PB of patients at different time points during or after therapy and PB of healthy controls. CONCLUSIONS In BCP-ALL patients, the B-cell compartment is drastically affected during treatment. Subsequent regeneration of BCPs and mature B-cells occurs at different time points during therapy and after stop of therapy. Immunophenotypically, BCP maturation in regenerating BM is similar to normal B-cell differentiation, indicating that MRD detection will not be hampered by aberrant immunophenotypes of regenerating BCPs. Importantly, no enhanced proliferation is observed in BCP subsets in BM and mature B-cells subsets in PB of patients during and after therapy. The lack of compensatory proliferation suggests that B-cell regeneration is due to a larger influx of non-committed stem cells into the B-cell lineage and indicates that a diverse immune repertoire will most likely be restored during recovery of the B-cell compartment. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Jeha, Sima, Frederick Behm, Deqing Pei, John T. Sandlund, Raul C. Ribeiro, Bassem I. Razzouk, Jeffrey E. Rubnitz et al. « Prognostic significance of CD20 expression in childhood B-cell precursor acute lymphoblastic leukemia ». Blood 108, n^o 10 (15 novembre 2006) : 3302–4. http://dx.doi.org/10.1182/blood-2006-04-016709.

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Abstract CD20 expression is associated with inferior survival in adults with acute lymphoblastic leukemia (ALL). We analyzed the prognostic impact of CD20 expression in 353 children with B-cell precursor ALL treated in 3 consecutive St Jude Total Therapy studies. CD20 expression (> 20%) was found in 169 patients (48%) and was more frequent in patients between 1 and 10 years of age than in those younger than 1 or older than 10 years (P = .001). None of 14 patients with MLL-AF4 expressed CD20. There was no association between CD20 expression and E2A-PBX, TEL-AML1, ploidy, white blood cell count at diagnosis, or sex. In contrast to the experience in adult ALL, our patients with CD20 expression tended to have a better treatment outcome than those without the expression: 5-year event-free survival 84% ± 2.9% versus 78% ± 3.1% (P = .08). These data suggest that CD20 expression is not associated with inferior outcome in pediatric patients treated with contemporary regimens.

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Lenk, Lennart, Fotini Vogiatzi, Michela Carlet, Christian Vokuhl, Gunnar Cario, Martin Schrappe, Irmela Jeremias et al. « CD79a Is Associated with Central Nervous System Infiltration of Pediatric B-Cell Precursor Acute Lymphoblastic Leukemia ». Blood 132, Supplement 1 (29 novembre 2018) : 386. http://dx.doi.org/10.1182/blood-2018-99-114595.

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Abstract Despite the advances in the treatment of pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL), infiltration of the central nervous system (CNS) remains a clinical challenge. Certain cytogenetic subtypes such as E2A-PBX1-and BCR-ABL-positive BCP-ALL confer a higher risk for CNS involvement initially and for CNS relapse. Novel strategies to predict CNS and to eradicate leukemic cells from the CNS are subjects of ongoing research. In order to identify targets with diagnostic and therapeutic relevance, comparative RNA-sequencing was performed with patient derived xenograft (PDX) blasts from 5 E2A-PBX1-positive patients, recovered from the bone marrow (BM) and from the CNS of NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice. Differential gene expression analysis revealed the upregulation of various genes of the pre-B cell receptor complex, particularly the signaling component CD79a (Igα) in blasts recovered from the CNS as compared to blasts from the BM. We then investigated the impact of CD79a on CNS infiltration in vivo and in patients. CD79a was downregulated by short-hairpin RNA (shRNA) mediated knockdown in the E2A-PBX1 positive cell line 697. Proliferation rates of 697-shCD79a cells and control-transfected 697 cells (697-shCtrl) in vitro were similar. Furthermore, NSG mice injected with 697-shCD79a cells showed comparable survival times, as well as similar blast infiltration in spleen and BM as animals injected with 697-shCtrl cells. However, downregulation of CD79a led to a significantly lower number of CNS-positive mice (4/15, 26%) as compared to control animals (7/10, 70%) (p=0.0486, Figure A). This indicates that CD79a is not critically involved in proliferation and peripheral engraftment, but in CNS infiltration of E2A-PBX1 positive 697 cells in vivo. To test if CD79a also affects CNS involvement in BCR-ABL-positive leukemia, a murine/murine transplantation model was used. B-cells isolated from CD79a-knockout (CD79a-KO) or wildtype mice (CD79a-Ctrl) were stably transfected with a BCR-ABL fusion gene and cultured independent of cytokines, thereby inducing malignant transformation. Both cell lines were subsequently injected into recipient NSG mice (n=8/group) and leukemic development was followed. The experiment was terminated when all control mice had developed leukemic symptoms and mice were analyzed for leukemic engraftment. A further CD79a-KO group was included for survival analysis. Median spleen volume as a surrogate of leukemic infiltration was significantly lower in mice injected with CD79a-KO as compared to CD79a-Ctrl cells (0.35 cm³ vs. 0.06 cm³; p=0.0001). Median blast percentages in spleens and BM were also markedly reduced (75.3% vs. 5.8%; p=0.0001 and 61.0% vs. 4.5%; p=0.0001, respectively). Importantly, none of the animals in the CD79a-KO group showed blasts in the CNS as assessed by histology whereas blasts were present in all of the animals in the CD79a-Ctrl group. Finally and most importantly, NSG-mice injected with CD79a-KO cells showed a highly significant prolongation in median survival as compared to mice with CD79a-Ctrl cells (29 days vs. 95 days; p=0.0001, Figure B). Altogether, these data suggest that in a model of BCR-ABL-positive leukemia, absence of CD79a impacts the engraftment of blasts in vivo, in the CNS and other leukemic niches. To further validate our findings in patient material, we measured CD79a protein expression in PDX cells from an E2A-PBX1- and a BCR-ABL-positive patient serially transplanted into NSG mice for three passages. For both entities and in all passages, CNS blasts showed a higher CD79a expression than blasts isolated from the bone marrow. In order to assess if CD79a can be used as a marker to predict CNS involvement in patients, CD79a mRNA levels were measured in a selected cohort of 98 pediatric BCP-ALL patients, which contained 26 CNS-positive patients matched to 72 CNS-negative patients. CNS-positive patients showed significantly higher mRNA levels of CD79a than CNS-negative patients (p=0.0225, unpaired t-test, Figure C) suggesting that CD79a may be of value as a potential diagnostic marker for initial CNS involvement in BCP-ALL. Our results indicate a role of CD79a in proliferation and CNS infiltration of BCP-ALL blasts in experimental settings and patients. We intend to prospectively evaluate CD79a as a prognostic marker, which may also be a therapeutic target in CNS-positive BCP-ALL. Disclosures No relevant conflicts of interest to declare.

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Feuchtinger, Tobias, Judith Feucht, Simone Kayser, David Gorodezki, Michaela Döring, Franziska Blaeschke, Hans Bösmüller et al. « Leukemia Related Co-Stimulation / Co-Inhibition Predict T-Cell Attack of Acute Lymphoblastic Leukemia Mediated By Blinatumomab ». Blood 126, n^o 23 (3 décembre 2015) : 3764. http://dx.doi.org/10.1182/blood.v126.23.3764.3764.

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Abstract Refractory B-precursor acute lymphoblastic leukemia (ALL) remains an unsolved therapeutic challenge. Various T-cell immunotherapies are promising options in relapsed/refractory B-ALL, like the CD19/CD3-bispecific T-cell engaging antibody Blinatumomab. Until now it has not been possible to determine critical factors for T-cell attack against leukemia that decide on in vivo response or non-response to treatment. Immune-checkpoint molecules regulate immune escape of malignant cells and antibody blockade of these inhibitory pathways enhances antitumor immune responses. Therefore, we investigated the role of co-stimulatory and co-inhibitory molecules for effector-target cell interactions and influence on T-cell attack against leukemia. CD19+ lymphoblast lines, primary pediatric B-ALL bone marrow blasts (n=10) and physiologic CD19+ CD10+ pre-B bone marrow precursors from healthy bone marrow were screened for surface expression of 20 different co-signaling molecules. Surface expression of PD-L1, PD-1, LAG3, CD40, CD86, CD27, CD70 and HVEM revealed differences in stimulatory and inhibitory profiles of pediatric ALL blasts as compared to physiologic cells. Pediatric ALL patients refractory to Blinatumomab-treatment (n=4) as well as patients with relapsed leukemia (n=7) showed increased expression of PD-L1 on blasts. Expression of exhaustion markers PD-1 and TIM-3 was significantly higher on patients' T cells as compared to healthy donors and is induced by T-cell attack against blasts. Blinatumomab-mediated T-cell function was examined in healthy donors as compared to pediatric patients with ALL through analysis of proliferation and effector function. Significant differences in Blinatumomab-induced T-cell function were found to be target-cell dependent and correlated to expression of co-signaling molecules on target cells. Blockade of inhibitory PD-1-PD-L and CTLA-4-CD80/CD86 interactions could further enhance effector T-cell function of healthy donors and patients whereas blockade of co-stimulatory CD28-CD80/86 interactions resulted in reduced T-cell effector and proliferation potential. Combined treatment with Blinatumomab and PD-1 blocking antibody Pembrolizumab was feasible and induced an anti-leukemic immune response in a 12 year old patient with refractory ALL. In conclusion, we show that regulation of T-cell activation and inhibition by co-signaling molecules guides the efficacy of T-cell attack against ALL. Inhibitory interactions between leukemia-induced checkpoint molecules on T cells and their counterparts on ALL regulate in vivo resistance to T-cell immunotherapy and will guide future therapeutic interventions. Disclosures Off Label Use: Pembrolizumab.

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Permikin, Zh V., A. M. Popov, T. Yu Verzhbitskaya, Т. О. Riger, O. R. Arakaev, A. A. Vlasova, Yu V. Olshanskaya et al. « Flow cytometric analysis of leukemic blast cells in pediatric B-cell precursor acute lymphoblastic leukemia with translocation t(12;21)(p13;q22)/ETV6-RUNX1 ». Oncohematology 13, n^o 4 (3 janvier 2019) : 93–103. http://dx.doi.org/10.17650/1818-8346-2019-13-4-93-103.

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The objective of the study was searching for surface antigen expression that could predict presence of translocation t(12;21)(p13;q22)/ETV6RUNX1 in pediatric B-cell precursor acute lymphoblastic leukemia patients.Results . ETV6-RUNX1 fusion gene transcript was revealed in 118 (22.4 %) out of 526 children with B-cell precursor acute lymphoblastic leukemia. Leukemic blast cells in ETV6-RUNX1-positive patients more frequently had high CD10 expression, myeloid markers co-expression , including CD13, CD33, CD117, and absence of CD20 than in ETV6-RUNX1-negative ones. Nevertheless diagnostic test performance characteristics of each single parameter was not strong enough for predicting the presence of translocation t(12;21)(p13;q22)/ETV6-RUNX1.Conclusion . Thus application of conventional set of immunological markers does not allow reliable distinguishing this patients’ subgroup. However antibodies panel enlargement, high degree of flow cytometry standardization and additional analytical methods can potentially improve applicability of antigen profile analysis for separation of patients with translocation t(12;21)(p13;q22)/ETV6-RUNX1.

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Purizaca, Jessica, Adriana Contreras-Quiroz, Elisa Dorantes-Acosta, Eduardo Vadillo, Lourdes Arriaga-Pizano, Silvestre Fuentes-Figueroa, Horacio Villagomez-Barragán et al. « Lymphoid Progenitor Cells from Childhood Acute Lymphoblastic Leukemia Are Functionally Deficient and Express High Levels of the Transcriptional Repressor Gfi-1 ». Clinical and Developmental Immunology 2013 (2013) : 1–12. http://dx.doi.org/10.1155/2013/349067.

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Acute lymphoblastic leukemia (ALL) is the most frequent malignancy of childhood. Substantial progress on understanding the cell hierarchy within ALL bone marrow (BM) has been recorded in the last few years, suggesting that both primitive cell fractions and committed lymphoid blasts with immature stem cell-like properties contain leukemia-initiating cells. Nevertheless, the biology of the early progenitors that initiate the lymphoid program remains elusive. The aim of the present study was to investigate the ability of lymphoid progenitors from B-cell precursor ALL BM to proliferate and undergo multilineage differentiation. By phenotype analyses,in vitroproliferation assays, and controlled culture systems, the lymphoid differentiation potentials were evaluated in BM primitive populations from B-cell precursor ALL pediatric patients. When compared to their normal counterparts, functional stem and progenitor cell contents were substantially reduced in ALL BM. Moreover, neither B nor NK or dendritic lymphoid-cell populations developed recurrently from highly purified ALL-lymphoid progenitors, and their proliferation and cell cycle status revealed limited proliferative capacity. Interestingly, a number of quiescence-associated transcription factors were elevated, including the transcriptional repressor Gfi-1, which was highly expressed in primitive CD34+cells. Together, our findings reveal major functional defects in the primitive hematopoietic component of ALL BM. A possible contribution of high levels of Gfi-1 expression in the regulation of the stem/progenitor cell biology is suggested.

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Marincevic-Zuniga, Y., V. Zachariadis, L. Cavelier, A. Castor, G. Barbany, E. Forestier, L. Fogelstrand et al. « PAX5-ESRRB is a recurrent fusion gene in B-cell precursor pediatric acute lymphoblastic leukemia ». Haematologica 101, n^o 1 (22 octobre 2015) : e20-e23. http://dx.doi.org/10.3324/haematol.2015.132332.

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Chaber, Radosław, Artur Gurgul, Grażyna Wróbel, Olga Haus, Anna Tomoń, Jerzy Kowalczyk, Tomasz Szmatoła et al. « Whole-genome DNA methylation characteristics in pediatric precursor B cell acute lymphoblastic leukemia (BCP ALL) ». PLOS ONE 12, n^o 11 (10 novembre 2017) : e0187422. http://dx.doi.org/10.1371/journal.pone.0187422.

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