BCR–ABL: a multi-faceted promoter of DNA mutation in chronic myelogeneous leukemia

Abstract

The role of the BCR–ABL oncogene in the progression of chronic myeloid leukemia (CML) to blast crisis (BC) is unknown. The appearance of chromosomal aberrations in patients with CML BC has led to many attempts to elucidate a mechanism whereby BCR–ABL affects DNA damage and repair. BCR–ABL-expressing cells have been found to accumulate genetic abnormalities, but the mechanism leading to this genomic instability is controversial. In this study, we review the effects of BCR–ABL on DNA repair mechanisms, centrosomes, checkpoint activation and apoptosis. BCR–ABL has diverse effects on these mechanisms, but which of these effects are necessary for the progression of CML to BC is still unresolved.

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

“…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.…”

A deep-sequencing study of chronic myeloid leukemia patients in blast crisis (BC-CML) detects mutations in 76.9% of cases

“…Patients diagnosed to be affected by acute promyelocitic leukemia, granulocytic sarcoma, secondary AML, myelodysplastic syndrome or Down syndrome, as well as patients with a pretreatment phase longer than 14 days, were excluded from this study. 4 The initial…”

“…The initial step for chronic phase is the occurrence of the Philadelphia chromosome and genetic instability caused by the BCR-ABL tyrosine kinase. 4 The second step is the acquisition of additional chromosomal aberrations or mutations of transcription factors by failed DNA repair processes. 5 However, at present, little is known about the molecular mechanisms underlying disease progression, but, most likely, activation of oncogenic factors and/or mutations leading to loss of function of tumor suppressor genes in hematopoietic stem cells are involved.…”

First-line treatment of chronic myeloid leukaemia

“…As secondline therapy they induce rapid responses with a median time to major cytogenetic response (MCyR) of approximately 3 months suggesting that in ECP it should be possible to rapidly induce CCyR and MMR in the majority of patients [Hochhaus et al 2008;Kantarjian et al 2007]. Given that they are more potent BCR-ABL inhibitors, more intensive kinase inhibition from the onset of initial treatment could reduce genomic instability induced by BCR-ABL and reduce the risk of subsequent mutations [Burke and Carroll, 2010]. By rapidly achieving MMR and suppressing genomic instability, the risk of early progression should then be minimized.…”