BCR/ABL promotes accumulation of chromosomal aberrations induced by oxidative and genotoxic stress

Koptyra, Mateusz; Cramer, Kimberly; Słupianek, Artur; Richardson, Christine; Skórski, Tomasz

doi:10.1038/leu.2008.78

Cited by 71 publications

(58 citation statements)

References 22 publications

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“…[38][39][40] There is also solid evidence for a direct link among BCR-ABL expression, genetic instability, and IM resistance. [41][42][43][44] Using an immortalized BCR-ABL-dependent cell line model resembling blast crisis cells, we also provided such evidence by showing that BCR-ABL overexpression catalyzes mutagenesis and IM resistance development to an even greater extent than chemical mutagenesis by ENU ( Figure 5B).…”

Section: Discussionmentioning

confidence: 62%

Low BCR-ABL expression levels in hematopoietic precursor cells enable persistence of chronic myeloid leukemia under imatinib

Kumari

Brendel

Hochhaus

et al. 2012

Blood

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Section: Discussionmentioning

confidence: 62%

Low BCR-ABL expression levels in hematopoietic precursor cells enable persistence of chronic myeloid leukemia under imatinib

Kumari

Brendel

Hochhaus

et al. 2012

Blood

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“…In contrast, LSCs from BCR-ABL1 -positive CML-CP and IDH1/2 mutation -positive AML accumulate high levels of ROS [5,10]. We reported that high levels of ROS in CML-CP LSCs induced oxidative DNA damage resulting in genomic instability which may produce imatinib-resistant BCR-ABL1 kinase mutants and additional chromosomal aberrations leading to the disease relapse and/or malignant progression [5,11,12].…”

Section: Discussionmentioning

confidence: 89%

Chronic myeloid leukemia stem cells display alterations in expression of genes involved in oxidative phosphorylation

Flis

Irvine

Copland

et al. 2012

Leukemia & Lymphoma

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Mitochondrial respiratory chain (MRC) consists of the protein complexes I, II, III, IV, and V to carry oxidative phosphorylation (OXPHOS), which depends on electron transport to generate ATP. Electron "leakage" from MRC generates reactive oxygen species (ROS). Chronic myeloid leukemia in chronic phase (CML-CP) stem cells (LSCs) produce high levels of mitochondrial ROS causing oxidative DNA damage resulting in genomic instability generating imatinibresistant BCR-ABL1 kinase mutants and additional chromosomal aberrations. Using global mRNA microarray analysis combined with Ingenuity pathway analysis we found that LSCs display enhanced expression of genes encoding MRC complexes I, II, IV, and V. However, expression of genes encoding complex III was deregulated. Treatment with imatinib did not correct the aberrant levels of MRC genes. Therefore we postulate that abnormal expression of MRC genes may facilitate electron "leakage" to promote production of ROS and accumulation of genomic instability in LSCs in imatinib-naive and imatinib-treated patients.

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“…11 TKI resistance in CML is related to the genetic instability caused by the BCR-ABL oncoprotein, acquisition of mutations and chromosomal aberrations, and selection of resistant clones by the continuous use of TKI. [21][22][23][24][25] Acquisition of BCR-ABL1 mutations seems to be an important phenomenon for progressing into advanced phases, particularly in lymphoid BP. 26 This may suggest that BCR-ABL1 KD mutations are a marker for genetic instability and indicate the presence of clones that have a higher propensity for disease progression.…”

Section: Discussionmentioning

confidence: 99%

Results of allogeneic hematopoietic stem cell transplantation for chronic myelogenous leukemia patients who failed tyrosine kinase inhibitors after developing BCR-ABL1 kinase domain mutations

Jabbour¹,

Cortes²,

Santos³

et al. 2011

Blood

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Hematopoietic stem cell transplantation (HSCT) is effective therapy for patients with chronic myelogenous leukemia (CML) but is now mostly indicated for patients who develop resistance to tyrosine kinase inhibitors (TKIs), which can be associated with point mutations in BCR-ABL1. We reviewed the outcomes of imatinib-resistant CML patients (chronic phase, n ‫؍‬ 34; accelerated phase [AP], n ‫؍‬ 9; and blast phase [BP], n ‫؍‬ 4) who underwent HSCT and had BCR-ABL1 sequencing. Mutations were found in 19 patients (40%); 15 of 19 had advanced CML (AP ؉ BP ؉ second chronic phase). Patients with mutations were more likely to transform to AP/BP at time of imatinib failure (69% vs 35%, P ‫؍‬ .03). Forty-two patients (89%) responded to HSCT: 32 (68%) had at least a major molecular response. The 2-year event-free survival was 36% and 58% (P ‫؍‬ .05) for the mutant and nonmutant groups, respectively; and the 2-year overall survival was 44% and 76% (P ‫؍‬ .02), respectively. HSCT is an important salvage option for TKI-resistant patients with or without BCR-ABL1 mutations. Patients with mutations were more likely to develop advanced disease and had worse outcomes after HSCT. HSCT should be considered early for patients deemed to have a low probability of responding to second-generation TKI. (Blood. 2011;117(13):3641-3647)

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BCR/ABL promotes accumulation of chromosomal aberrations induced by oxidative and genotoxic stress

Cited by 71 publications

References 22 publications

Low BCR-ABL expression levels in hematopoietic precursor cells enable persistence of chronic myeloid leukemia under imatinib

Low BCR-ABL expression levels in hematopoietic precursor cells enable persistence of chronic myeloid leukemia under imatinib

Chronic myeloid leukemia stem cells display alterations in expression of genes involved in oxidative phosphorylation

Results of allogeneic hematopoietic stem cell transplantation for chronic myelogenous leukemia patients who failed tyrosine kinase inhibitors after developing BCR-ABL1 kinase domain mutations

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