Fusion tyrosine kinases: a result and cause of genomic instability

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

“…2,6-10 BCR/ABL kinase results from unfaithful repair of two DNA double-strand breaks (DSBs) generating t(9;22), which may represent a random event or result from preexisting conditions associated with genomic instability. 5,11 Therefore, additional chromosomal aberrations accumulated during the course of CML may be promoted by preexisting condition responsible for t(9;22) and/or by BCR/ABL. The latter statement is supported by reports that BCR/ABL-positive cells acquire more DSBs than Figure 1 Representative examples of SKY analyses of chromosomal aberrations described in Table 1 Letters to the Editor normal counterparts in response to endogenous reactive oxygen species (ROS) and genotoxic treatment [12][13][14][15] and that BCR/ABL stimulates the efficiency but decreases the fidelity of DSB repair mechanisms.…”

“…12,13,22 In addition, leukemia cells have enhanced probability to accumulate chromosomal errors due to a negative effect of BCR/ABL kinase on the fidelity of DSBs repair. 5 The potential role for unfaithful DSB repair mechanisms can be suggested, because BCR/ABL kinase enhances the expression of RAD51 and downregulates DNA-PKcs, key elements in two major mechanisms of DSBs repair, homologous recombination repair and non-homologous end-joining, respectively. 17,23 Interestingly, overexpression of RAD51 and the inhibition of DNA-PKcs promoted aneuploidy and multiple chromosomal rearrangements.…”

“…3,4 The most frequently noticed chromosomal errors involve numerical gains and losses of chromosomes, isochromosome i(17q) causing loss of p53, reciprocal translocations 3;21 and 7;11 generating AML-1/Evi-1 and NUP98/HOXA9 fusion proteins, respectively, and other translocations and inversions associated with AML/myelodysplasia, such as inv(3) and t (15;17). 5 Clinical and experimental observations strongly Table 1 BCR/ABL promotes accumulation of ROS and radiation-induced chromosomal aberrations in vitro and in vivo…”

Fusion Tyrosine Kinase NPM-ALK Deregulates MSH2 and Suppresses DNA Mismatch Repair Function

“…[47][48][49][50][51] It has been recently shown that expression of the fusion tyrosine kinase BCR/ABL reduced the MMR response to single base mismatches and DNA damage-induced signaling. 52 Nevertheless, how these oncogenic tyrosine kinases impair MMR function is largely unknown.…”

Chronic myeloid leukemia – some topical issues

“…5 However, the Bcr-Abl kinase itself enhances genomic instability leading to accumulation of secondary genetic errors, which may be responsible for resistance to small molecule drugs, such as IM, and transformation to blast crisis (BC). 6 The BCR-ABL signalling network is still incompletely defined and it is entirely possible that the action of established Bcr-Abl inhibitors could be enhanced by combining them with other kinase inhibitors. Conversely, the clinical efficacy in CML of the known Bcr-Abl inhibitors could be due in part to inhibition of kinases other than Bcr-Abl.…”