scholarly journals A mutation in the Icsbp1 gene causes susceptibility to infection and a chronic myeloid leukemia–like syndrome in BXH-2 mice

2005 ◽  
Vol 201 (6) ◽  
pp. 881-890 ◽  
Author(s):  
Karine Turcotte ◽  
Susan Gauthier ◽  
Ashleigh Tuite ◽  
Alaka Mullick ◽  
Danielle Malo ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Insertional Mutagenesis ◽  
Consensus Sequence ◽  
Interferon Γ ◽  
Chromosome 8 ◽  
Leukemic Cells ◽  
Interleukin 12 ◽  
Recessive Mutation ◽  
Loss Of Function

BXH-2 mice develop a fatal myeloid leukemia by a two-step mutagenic process. First, a BXH-2–specific recessive mutation causes a myeloproliferative syndrome. Second, retroviral insertions alter oncogenes or tumor suppressors, resulting in clonal expansion of leukemic cells. We have identified a recessive locus on chromosome 8 (Myls) that is responsible for myeloproliferation in BXH-2. This Myls interval has been narrowed down to 2 Mb and found to contain several positional candidates, including the interferon consensus sequence–binding protein 1 gene (Icsbp, also known as interferon regulatory factor 8 [IRF8]). We show that BXH-2 mice carry a mutation (915 C to T) resulting in an arginine-to-cysteine substitution at position 294 within the predicted IRF association domain of the protein. Although expression of Icsbp1 mRNA transcripts is normal in BXH-2 splenocytes, these cells are unable to produce interleukin 12 and interferon-γ in response to activating stimuli, confirming that R294C behaves as a loss-of-function mutation. Myeloproliferation in BXH-2 mice is concomitant to increased susceptibility to Mycobacterium bovis (BCG) despite the presence of resistance alleles at the Nramp1 locus. These results suggest a two-step model for chronic myeloid leukemia in BXH-2, in which inactivation of Icsbp1 predisposes to myeloproliferation and immunodeficiency. This event is required for retroviral replication, and subsequent insertional mutagenesis that causes leukemia in BXH-2 mice.

Interaction of a Novel Signaling Protein (AHI-1) with BCR-ABL Modulates BCR-ABL Transforming Activity and Imatinib Response of Chronic Myeloid Leukemia Progenitor Cells.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 467-467
Author(s):  
Yun Zhao ◽  
Leon Zhou ◽  
Ashley Ringrose ◽  
Ann E.-J. Lin ◽  
Erin Kennah ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Progenitor Cells ◽  
Myeloid Leukemia ◽  
Insertional Mutagenesis ◽  
B Cell Lymphoma ◽  
Suspension Cultures ◽  
Leukemic Cells ◽  
Physical Interaction ◽  
Liquid Suspension ◽  
Semi Solid

Abstract Ahi-1 (Abelson helper integration site 1) is a novel gene that was initially identified by provirus insertional mutagenesis in v-abl-induced murine pre-B cell lymphoma as a candidate cooperate oncogene. The Ahi-1 protein has a SH3 domain, multiple SH3 binding sites and WD-repeat domains, suggesting novel signaling activities. We recently demonstrated that Ahi-1/AHI-1 transcript levels are highly deregulated in human leukemic cells, particularly in highly enriched populations of BCR-ABL+ leukemic stem cells from patients with chronic myeloid leukemia (CML) where levels of BCR-ABL transcripts are also elevated. Interestingly, overexpression of Ahi-1 alone in primitive murine hematopotic cells confers a proliferative advantage in vitro and induces a lethal leukemia in vivo; these effects can be enhanced by BCR-ABL, a fusion oncogene that drives CML pathogenesis. To investigate whether deregulated expression of AHI-1 may directly contribute to BCR-ABL-mediated transformation and altered signaling pathways in human CML, knockdown of AHI-1 expression in K562 cells, a cell line that was derived from a patient with CML and that is characterized by highly increased expression of AHI-1, was performed using retroviral-mediated RNA interference. Retroviral-mediated suppression specifically inhibited endogenous AHI-1 expression in transduced cells by 70% as evaluated by Q-RT-PCR and Western blot analyses. It further caused a significant reduction in their growth factor independence in semi-solid cultures (up to 5-fold, P< 0.01) and in single cell cultures (2-fold, P< 0.05) by comparison to cells transduced with a control vector. Importantly, lentiviral-mediated suppression of AHI-1 in BCR-ABL transduced primitive human cord blood (CB) cells (lin−CD34+) further showed a significant reduction of up to 10-fold (P< 0.01) in colony-forming cell (CFC) output and up to 5-fold (P< 0.01) in liquid suspension cultures as compared to BCR-ABL transduced cells alone. In addition, suppression of AHI-1 expression also resulted in a reduction in CFC output in lin−CD34+ stem/progenitor cells from CML patients (n=3). Strikingly, co-expression of Ahi-1 in BCR-ABL inducible BaF3 cells immediately reverses growth deficiencies exhibited by down-regulation of BCR-ABL in both semi-solid cultures (>50-fold) and in liquid suspension cultures in the absence of IL-3 (>30-fold), and is associated with sustained phosphorylation of BCR-ABL and enhanced activation of JAK2/STAT5. Moreover, a direct physical interaction between AHI-1 and BCR-ABL at endogenous levels has now been identified in CML cells; this interaction complex is also associated with a 120 kDa tyrosine phosphorylated protein. In addition, significant changes in imatinib (IM, an inhibitor of the BCR-ABL) response have been further demonstrated in Ahi-1 transduced BCR-ABL inducible BaF3 cells (P< 0.01) and in AHI-1 suppressed CML stem/progenitor cells (n=3). These findings provide strong evidence that Ahi-1/AHI-1 interacts with BCR-ABL to form an interaction complex and that this interaction complex further modulates altered BCR-ABL signaling and transforming activities of CML progenitor cells, including their response to IM.

scholarly journals Development of BCR-ABL1 Transgenic Zebrafish Model Reproducing Chronic Myeloid Leukemia (CML) Like-Disease and Providing a New Insight into CML Mechanisms

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 445
Author(s):  
Daniela Zizioli ◽  
Simona Bernardi ◽  
Marco Varinelli ◽  
Mirko Farina ◽  
Luca Mignani ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Fusion Gene ◽  
Philadelphia Chromosome ◽  
Leukemic Cells ◽  
Transgenic Zebrafish ◽  
Hematopoietic Tissue ◽  
Zebrafish Model ◽  
Altered Expression

Zebrafish has proven to be a versatile and reliable experimental in vivo tool to study human hematopoiesis and model hematological malignancies. Transgenic technologies enable the generation of specific leukemia types by the expression of human oncogenes under specific promoters. Using this technology, a variety of myeloid and lymphoid malignancies zebrafish models have been described. Chronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasia characterized by the BCR-ABL1 fusion gene, derived from the t (9;22) translocation causing the Philadelphia Chromosome (Ph). The BCR-ABL1 protein is a constitutively activated tyrosine kinas inducing the leukemogenesis and resulting in an accumulation of immature leukemic cells into bone marrow and peripheral blood. To model Ph+ CML, a transgenic zebrafish line expressing the human BCR-ABL1 was generated by the Gal4/UAS system, and then crossed with the hsp70-Gal4 transgenic line. The new line named (BCR-ABL1pUAS:CFP/hsp70-Gal4), presented altered expression of hematopoietic markers during embryonic development compared to controls and transgenic larvae showed proliferating hematopoietic cells in the caudal hematopoietic tissue (CHT). The present transgenic zebrafish would be a robust CML model and a high-throughput drug screening tool.

scholarly journals Molecular analysis of relapse in chronic myeloid leukemia after allogeneic bone marrow transplantation

Blood ◽  
1987 ◽  
Vol 70 (3) ◽  
pp. 873-876 ◽  
Author(s):  
TS Ganesan ◽  
GL Min ◽  
JM Goldman ◽  
BD Young
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Chronic Myeloid Leukemia ◽  
Marrow Transplantation ◽  
Myeloid Leukemia ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone Marrow ◽  
Leukemic Cells ◽  
Allogeneic Bone ◽  
Leukemic Clone

Abstract Four patients with Philadelphia (Ph′) positive chronic myeloid leukemia (CML) were studied before, after, and on relapse following allogeneic bone marrow transplantation (BMT). Southern analysis of DNA from cells collected before and at relapse after BMT was performed in order to investigate the origin of the leukemia at relapse. Using minisatellite probes we showed that the relapse occurred in cells of host origin in all four patients and this was confirmed with a Y chromosome specific probe in two male patients who had a female donor. Furthermore, using two probes for the breakpoint cluster region (bcr) on chromosome 22, we showed that leukemic cells at relapse bore identical rearrangements to those in the disease at time of presentation of each patient. We conclude that relapse in all four patients is due to re-emergence of the original leukemic clone.

scholarly journals Molecular analysis of relapse in chronic myeloid leukemia after allogeneic bone marrow transplantation

Blood ◽  
1987 ◽  
Vol 70 (3) ◽  
pp. 873-876
Author(s):  
TS Ganesan ◽  
GL Min ◽  
JM Goldman ◽  
BD Young
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Chronic Myeloid Leukemia ◽  
Marrow Transplantation ◽  
Myeloid Leukemia ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone Marrow ◽  
Leukemic Cells ◽  
Allogeneic Bone ◽  
Leukemic Clone

Four patients with Philadelphia (Ph′) positive chronic myeloid leukemia (CML) were studied before, after, and on relapse following allogeneic bone marrow transplantation (BMT). Southern analysis of DNA from cells collected before and at relapse after BMT was performed in order to investigate the origin of the leukemia at relapse. Using minisatellite probes we showed that the relapse occurred in cells of host origin in all four patients and this was confirmed with a Y chromosome specific probe in two male patients who had a female donor. Furthermore, using two probes for the breakpoint cluster region (bcr) on chromosome 22, we showed that leukemic cells at relapse bore identical rearrangements to those in the disease at time of presentation of each patient. We conclude that relapse in all four patients is due to re-emergence of the original leukemic clone.

Long-term treatment-free remission of chronic myeloid leukemia with falling levels of residual leukemic cells

Leukemia ◽  
2018 ◽  
Vol 32 (12) ◽  
pp. 2572-2579 ◽  
Author(s):  
David M. Ross ◽  
◽  
Ilaria S. Pagani ◽  
Naranie Shanmuganathan ◽  
Chung H. Kok ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Term Treatment ◽  
Leukemic Cells ◽  
Long Term Treatment ◽  
Treatment Free Remission

scholarly journals Ph-negative chronic myeloid leukemia: molecular analysis of ABL insertion into M-BCR on chromosome 22

Blood ◽  
1990 ◽  
Vol 76 (9) ◽  
pp. 1812-1818 ◽  
Author(s):  
CM Morris ◽  
N Heisterkamp ◽  
MA Kennedy ◽  
PH Fitzgerald ◽  
J Groffen
Keyword(s):  
In Situ Hybridization ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Fusion Gene ◽  
Repetitive Sequences ◽  
Chromosome 9 ◽  
Leukemic Cells ◽  
Chromosome 22 ◽  
Chromosome 9Q34

Abstract Leukemic cells from a patient with Ph-negative chronic myeloid leukemia (CML) had a normal karyotype. M-BCR was rearranged and chromosome in situ hybridization showed an ABL insertion between 5′ and 3′ M-BCR on an apparently normal chromosome 22. The association of 5′ BCR and 3′ ABL at the 5′ junction of the chromosome 9 insert was typical of that found for the BCR-ABL fusion gene in other patients with the standard t(9;22) and CML. With an M-bcr-3′ probe, we cloned and characterized a 3′ junction fragment. Field inversion gel electrophoresis and chromosome in situ hybridization studies using a probe isolated from genomic DNA 5′ of the junction showed that 3′ M-BCR was joined to a region of chromosome 9q34 rich in repetitive sequences and lying some distance 3′ of ABL. The chromosome 9 insert was at least 329 kilobases long and included 3′ ABL and a larger portion of chromosome 9q34. Our results allowed us to exclude transposon- or retroviral-mediated insertion of ABL into chromosome 22. Instead, we favored a two- translocation model in which a second translocation reconstituted a standard t(9;22)(q34;q11) but left the chromosome 9 insert, including 3′ ABL, in chromosome 22.

scholarly journals Phenotypic heterogeneity of primitive leukemic hematopoietic cells in patients with chronic myeloid leukemia

Blood ◽  
1992 ◽  
Vol 80 (10) ◽  
pp. 2522-2530 ◽  
Author(s):  
C Udomsakdi ◽  
CJ Eaves ◽  
PM Lansdorp ◽  
AC Eaves
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Philadelphia Chromosome ◽  
Significant Proportion ◽  
Hematopoietic Cells ◽  
Chronic Phase ◽  
Leukemic Cells ◽  
Clonogenic Cell ◽  
Clonogenic Cells

Abstract The peripheral blood of chronic myeloid leukemia (CML) patients with chronic-phase disease and elevated white blood cell (WBC) counts typically contains markedly increased numbers of a variety of neoplastic pluripotent and lineage-restricted hematopoietic progenitors. These include cells detected in standard colony assays as well as their more primitive precursors. The latter are referred to as long-term culture-initiating cells (LTC-IC) because of their ability to generate clonogenic cell progeny detectable after a minimum of 5 weeks incubation on competent fibroblast feeder layers. In this study, we have investigated a number of the properties of the LTC-IC and clonogenic cells present in the blood of such CML patients with high WBC counts. This included an analysis of the light scattering properties of these progenitors, as well as their expression of CD34 and HLA-DR, Rhodamine-123 staining, and in vitro sensitivity to 4- hydroperoxycyclophosphamide. In the case of LTC-IC, the production of different types of lineage-restricted and multipotent progeny was also analyzed. Most of the circulating LTC-IC and clonogenic cells in the CML patients studied (on average approximately 70% and approximately 90%, respectively) showed features of proliferating or activated cells. This is in marked contrast to the majority of progenitors in the blood of normal individuals and most of the LTC-IC in normal marrow, all of which exhibit a phenotype expected of quiescent cells. Interestingly, a significant proportion of the circulating clonogenic cells and LTC-IC in the CML samples studied (on average approximately 10% and approximately 30%, respectively) appeared to be phenotypically similar to normal circulating progenitors, although their absolute numbers were indicative of a neoplastic origin. Both phenotypes of circulating CML clonogenic cells and LTC-IC could be obtained at approximately 10% to 20% purity by differential multiparameter sorting. These findings suggest that expansion of the Philadelphia chromosome-positive clone at the level of the earliest types of hematopoietic cells results from the activation of mechanisms that enable some, but not all, signals that block the cycling of normal stem cells to be bypassed or overcome. In addition, they provide strategies for purifying these primitive leukemic cells that should facilitate further analysis of the mechanisms underlying their abnormal proliferative behavior.

Plasma RNA Is More Reliable Than Peripheral Blood Cells for Monitoring Molecular Response to Imatinib in Patients with Chronic Myeloid Leukemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2007-2007
Author(s):  
W. Ma ◽  
R. Tseng ◽  
M. Gorre ◽  
I. Jilani ◽  
M. Keating ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
The Body ◽  
Leukemic Cells ◽  
Molecular Response ◽  
Plasma Samples ◽  
Pcr Assay ◽  
Qrt Pcr ◽  
Reliable Source

Abstract With the use of imatinib for treatment of chronic myeloid leukemia (CML), monitoring treatment response and quantifying leukemic cells in the body by specific detection of the bcr-abl fusion gene or its mRNA is becoming the standard of care. The high frequency of complete cytogenetic response in CML patients has led to reliance on quantitative reverse-transcription-polymerase chain reaction (qRT-PCR) for detection of the bcr-abl mRNA when monitoring therapy. Peripheral blood (PB) and bone marrow (BM) specimens are usually used for qRT-PCR assays. However, standardization of the qRT-PCR assay and issues regarding sampling and the number of cells that need to be analyzed make reliance on such assays problematic. We previously showed that leukemic cells pour their RNA, DNA, and protein into circulation and, because of their high turnover rate, enrich the plasma with these components. We also hypothesize that plasma mRNA reflects disease activity in the entire body rather than the few cells in the analyzed sample, making plasma a more reliable source than PB cells. In this study we compared qRT-PCR results obtained from PB cells with those obtained from plasma in CML patients being treated with imatinib. PB cell and plasma samples obtained at baseline (n=67) and at 3 (n=43), 6 (n=22), 9 (n=19), and 12 (n=9) months of therapy were compared. The same qRT-PCR assay was used for cell- and plasma-based testing. However, the RNA extraction from plasma was standardized by using equal amounts from all samples and the RNA from 50μL plasma for each qRT-PCR assay. All plasma samples from CML patients were positive at baseline, whereas testing of more than 180 plasma samples from normal individuals or patients with leukemia other than CML showed no detectable bcr-abl transcript. In CML patients, the pattern of changes with therapy in the qRT-PCR in the plasma paralleled that obtained from cell-based testing. At 3 months, all patients who were negative by plasma-based testing were also negative by cell-based testing, whereas 6 of the 14 negative patients by cell-based testing were positive by plasma-based testing. At 6 months of therapy, 8 patients were negative by cell-based testing and all but 1 of these were negative by plasma; this patient was positive by plasma-based testing and became positive by cell-based testing at 9 and 12 months. 10 patients were negative by plasma-based testing at 6 months, 3 of whom were positive by cell-based testing. However, 2 of these 3 became negative by cell-based testing at 9 months and remained negative at 12 months. At 9 months of therapy, 9 patients were negative by cell-based testing, of whom 3 were positive by plasma-based testing; these 3 became positive by cell-based testing at 12 months. 8 patients were negative by plasma-based testing at 9 months, 1 of whom was positive by cell-based qRT-PCR. However, this patient became negative by cell-based testing at 12 months. This data show not only that plasma is a reliable source for testing and monitoring patients with CML, but that it is more reliable than PB cells for monitoring molecular response in CML. Furthermore, because plasma-based test results can be reported as mRNA copies/μL plasma, this platform has the potential to allow better standardization of testing among laboratories.

DC-Based Vaccines Show in-Vitro Activity against Chronic Myeloid Leukemia Cells

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4276-4276
Author(s):  
Yuen-Fen Tan ◽  
Soon-Keng Cheong ◽  
Chooi-Fun Leong ◽  
SAW Fadhilah
Keyword(s):  
T Cells ◽  
Immune System ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Leukemic Cells ◽  
Gm Csf ◽  
Dc Vaccine ◽  
Hla Dr

Abstract Chronic Myeloid leukemia is a common myeloproliferative disease. Despite recent advances in targeted therapy, only 7–12% of patients achieve molecular remission. Leukemic cells arrange multiple mechanisms to avoid recognition by the immune system. Dendritic cells (DC) are professional antigen presenting cells of the immune system playing a crucial role in the induction of anti-tumor responses. The use of DC is an attractive immunotherapeutic strategy against cancers, especially in minimal residual disease state. In this study, DC vaccine against chronic myeloid leukemia was generated and evaluated in-vitro. Monocytes were isolated and enriched from peripheral blood. These monocytes were subsequently cultured in RPMI medium supplemented with GM-CSF and IL-4 to induce them to become DC. These DC were then co-cultured with tumor lysates obtained from CML cell line in culture medium supplemented with GM-CSF, IL-4 and TNF alpha to become DC-based CML vaccine. The generated DC-based CML vaccines retained their DC morphology, showed strong expression of CD 86 and HLA-DR, and were negative for CD14. Mixed lymphocyte reaction indicated that the generated DC-based CML vaccines were capable of inducing proliferative responses to allogeneic lymphocytes. DC-based CML vaccines were shown to stimulate T cells to express DC-ligands, ie CD28 and CD154, as well as HLA-DR, CD71 and CD 25. In addition, the stimulated T cells were cytotoxic to CML cells used to prepare tumor lysates.

Identification of Rab5 as a Gene Involved in Chronic Myeloid Leukemia (CML) Progression.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3470-3470
Author(s):  
Daniela Cilloni ◽  
Monica Pradotto ◽  
Francesca Messa ◽  
Francesca Arruga ◽  
Enrico Bracco ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Western Blot ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Blast Crisis ◽  
Small Gtpases ◽  
Loss Of Function ◽  
Imatinib Resistance ◽  
Protein Levels

Abstract Abstract 3470 Poster Board III-358 The role of Bcr-Abl in the pathogenesis of Chronic Myeloid Leukemia (CML) is well established, however, the mechanisms leading to CML progression remain poorly understood. By using our model of transgenic Drosophila Melanogaster (Dm) for human Bcr-Abl driven CML we have identified Rab5 as a gene involved in the regulation of CML progression. The Rab5 is a member of gene family small GTPases which are involved in the regulation of vesicular transport. Lately several important reports have linked some members of the Rab family to invesivness and migration of cancer cells. Rab5 is associate with alpha-integrin subunits and modulates their endosomal traffic and subcellular localization. We have observed that a loss of function of Rab5 gene have induced a worsening of the CML phenotype generated by hBcr-Abl expression. In contrast, Rab gain of function rescued Bcr-Abl phenotype. The aim of the study was to evaluate the expression of Rab5 in CML cells to better understand if a potential correlation with progression, which has been observed in the model, could be confirmed in patients. Methods Rab5 gene expression was measured by Real Time PCR in 90 samples from 80 CML patients (32 PB and 58 BM). Among those, 53 are collected at diagnosis (19 of 53 patients have been enrolled in TOPS study). In addition, 9 samples from in CP patients have been collected at the time of imatinib resistance, 7 in accelerated phase and 11 in BC. In 14 patients, genes expression was analyzed during remission as, well. In parallel, 21 healthy donors (10 PB and 11 BM) have been evaluated. Rab5 protein expression was investigated by Western Blot and Immunofluorescence. We have also utilized K562 transfected with Rab5 plasmid, which we have generated to gain insight about the effects of Rab5 on cell proliferation and apoptosis. Results Rab5 transfection and overexpression in K562 significantly reduced proliferation and affected apoptosis. We found that in CML patients Rab5 expression levels were significantly decreased in either BM or PB (p<0.001 and p<0.0001) as compared to healthy subjects. Furthermore, in blast crisis samples we have found Rab5 transcripts levels to be further decreased. In contrast, at the time of remission, the transcript levels were comparable to normal values. Our preliminary analysis of samples from TOPS trial have shown a trend that Rab5 levels are lower among those patients achieving MMR by 12 months, when compared to the group of patients non achieving MMR on 400 mg, but that difference was not statistically significant (p=0.2). Among those randomized to receive imatinib 800 mg the difference was statistically significant with a median value among those achieving MMR of 1.27 vs 2.14 in the group without MMR (p=0.04). The protein levels have been analyzed by Western Blot and immunofluorescence and allow us to show detectable levels of Rab5 in samples collected at remission, but undetectable levels in course of active CML disease. Although preliminary, our results show a significant decrease of Rab5 expression in blast crisis samples, when compared to CP CML and healthy volunteers, which suggest a role of Rab5 in slowing down or suppressing a progression. Surprisingly, among CP CML patients the responders to TKI therapy have been detected to express a lower level of Rab5 than non responders. We are conducting further studies to better explain these data, which we find intriguing and suggesting that molecular factors involved in the regulation of CML progression could be uncoupled from the mechanisms regulating response to TKI therapy. Supported by Novartis Oncology, Clinical Development, TOPS Clinical Correlative Studies Network Disclosures No relevant conflicts of interest to declare.

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