BCR-ABL expression in leukemic progenitors and primitive stem cells of patients with chronic myeloid leukemia

Chomel, Jean‐Claude; Sorel, Nathalie; Guilhot, Joëlle; Guilhot, François; Turhan, Ali G.

doi:10.1182/blood-2011-12-396226

Cited by 23 publications

(22 citation statements)

References 8 publications

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“…They further showed that high levels of MYC are harmful for LSCs, and ubiquitination (degradation) of MYC by ubiquitin ligase Fbw7 keeps MYC levels in check in LSCs [162]. This provides a rationale for the constrained BCR-ABL1 kinase activity observed in quiescent LSCs [113] and selection of low BCR-ABL1 expression in TKI-refractive LSCs [102,103] (suggesting that enhanced BCR-ABL1 signalling is toxic for quiescent cells). These findings, coupled with MYC's established role in myeloid differentiation [163], present deregulation of MYC as a strong candidate for BC transformation in CML.…”

Section: Mycmentioning

confidence: 97%

“…They showed that potent TKIs failed to wipeout CML-LSCs, that the bone marrow environment may offer sanctuary against TKIs and that withdrawal of TKIs leads to reconstitution of leukaemic expansion [100,101]. It was recently reported that therapy-refractory LSCs exhibit a bias for low BCR-ABL1 expression [102,103]. So, LSCs that 'keep their kinase activity down' may survive TKI therapy and, perhaps, a non-kinase BCR-ABL1-dependent mechanism may protect LSCs (which has yet to be ruled out).…”

Section: Stem Cellsmentioning

confidence: 99%

“…When Wnt is bound to its receptor Frizzled, β-catenin is protected from ubiquitin-mediated degradation and is free to translocate to the nucleus and activate its target genes [105]. β-catenin tyrosine phosphorylation by BCR-ABL1 also leads to its stabilisation and increased levels and activity in CML [102]. Although dispensable for maintenance of LSCs and HSCs [106][107][108], therapeutic targeting of this pathway can cooperate with TKIs to delay disease onset and deplete CML-LSCs in CML mouse models [107].…”

Section: β-Cateninmentioning

confidence: 99%

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Natural course and biology of CML

2015

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Chronic myeloid leukaemia (CML) is a myeloproliferative disorder arising in the haemopoietic stem cell (HSC) compartment. This disease is characterised by a reciprocal t(9;22) chromosomal translocation, resulting in the formation of the Philadelphia (Ph) chromosome containing the BCR-ABL1 gene. As such, diagnosis and monitoring of disease involves detection of BCR-ABL1. It is the BCR-ABL1 protein, in particular its constitutively active tyrosine kinase activity, that forges the pathogenesis of CML. This aberrant kinase signalling activates downstream targets that reprogram the cell to cause uncontrolled proliferation and results in myeloid hyperplasia and 'indolent' symptoms of chronic phase (CP) CML. Without successful intervention, the disease will progress into blast crisis (BC), resembling an acute leukaemia. This advanced disease stage takes on an aggressive phenotype and is almost always fatal. The cell biology of CML is also centred on BCR-ABL1. The presence of BCR-ABL1 can explain virtually all the cellular features of the leukaemia (enhanced cell growth, inhibition of apoptosis, altered cell adhesion, growth factor independence, impaired genomic surveillance and differentiation). This article provides an overview of the clinical and cell biology of CML, and highlights key findings and unanswered questions essential for understanding this disease.

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Section: Mycmentioning

confidence: 97%

Section: Stem Cellsmentioning

confidence: 99%

Section: β-Cateninmentioning

confidence: 99%

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Natural course and biology of CML

2015

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“…In CML, the prevalence of M-bcr is higher than m-bcr (Press et al, 2007). In contrary, ALL patients showed a higher prevalence of m-bcr (Chomel et al, 2012). Although the distribution of BCR-ABL subtype have been studied in CML and ALL separately (Hanfstein et al, 2012;Marin et al, 2012), few studies have investigated the BCR-ABL subtype distribution in CML-CP, CML-BP and ALL patient simultaneity and there is still lack of data on the impact of BCR-ABL subtypes in progression of CML and ALL.…”

mentioning

confidence: 90%

Clinical Significance of BCR-ABL Fusion Gene Subtypes in Chronic Myelogenous and Acute Lymphoblastic Leukemias

Zhou²,

Zhou³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Asian Pac J Cancer Prev, 15 (22), 9961-9966 IntroductionThe Philadelphia chromosome (Ph), t (9; 22) (q34; q11.2) is transcribed into a fusion gene, BCR-ABL (Awan et al., 2012;Sabir et al., 2012). This translocation is one of the most common genetic abnormalities detected in leukemia. The site of the breakpoint in the BCR gene may influence the phenotype of diseases. In the vast majority of patients, the breakpoints in the BCR gene are clustered within three well-defined regions: (I) a 55 kb sequence of the first intron, called the minor breakpoint cluster region (m-bcr); (II) a 5.8 kb region spanning exons 12-16, called the major breakpoint cluster region (M-bcr), and finally; (III) intron 19, called μ-bcr. The resultant fusion transcript (e1-a2) (m-bcr) encodes a 190 kDa chimeric protein (p190), and in cases of M-bcr, codes a 210 kDa chimeric protein (p210) and in cases of μ-bcr, a 230 kDa protein (p230) (Fausel, 2007). Large studies indicated that BCR-ABL fusion gene is a highly useful diagnostic tool that controls the effectiveness of the chronic myelogenous

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“…Consistent with this, residual Ph + progenitors isolated from CML patients in MMR or complete molecular response (CMR) seem to have lower BCR-ABL1 transcript levels than are found in similar progenitors from patients at diagnosis. 26,27 After the initiation of TKI therapy, BCR-ABL1 transcripts measured in blood or BM decline logarithmically with several distinct phases or slopes. 28,29 Although different mathematic models can be derived from these data, a consensus interpretation is that the initial rapid decline in transcripts over the first ~ 6 months of treatment represents elimination of differentiated leukemic cells, with slower phases over subsequent years reflecting depletion of immature progenitors and perhaps LSCs.…”

Section: Whither CML Stem Cells?mentioning

confidence: 99%

Alternative approaches to eradicating the malignant clone in chronic myeloid leukemia: tyrosine-kinase inhibitor combinations and beyond

Ahmed

Etten

2013

Hematology

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In patients with chronic myeloid leukemia (CML) in chronic phase who have achieved complete molecular remission on imatinib therapy, clinical trials from France and Australia have demonstrated that the majority experience prompt molecular relapse of their leukemia upon discontinuation of the drug, showing that long-term monotherapy with tyrosine kinase inhibitors is not curative in the majority of patients with CML. This has focused attention on strategies to eradicate residual disease in CML that is presumed to arise from malignant Ph+ stem cells, which should result in permanent cure and long-term leukemia-free survival. Here, we review the evidence that targeting CML stem cells will be of clinical benefit and discuss pharmacological and immunological approaches to accomplish this goal. Where possible, we link preclinical studies of CML stem cell biology to emerging results from clinical trials of agents that may target these cells.

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BCR-ABL expression in leukemic progenitors and primitive stem cells of patients with chronic myeloid leukemia

Cited by 23 publications

References 8 publications

Natural course and biology of CML

Natural course and biology of CML

Clinical Significance of BCR-ABL Fusion Gene Subtypes in Chronic Myelogenous and Acute Lymphoblastic Leukemias

Alternative approaches to eradicating the malignant clone in chronic myeloid leukemia: tyrosine-kinase inhibitor combinations and beyond

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