BCR/ABL and other kinases from chronic myeloproliferative disorders stimulate single-strand annealing, an unfaithful DNA double-strand break repair.
BCR/ABL and other kinases from chronic myeloproliferative disorders stimulate single-strand annealing, an unfaithful DNA double-strand break repair.
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DOI：
10.1158/0008-5472.can-08-1101
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发表时间：
2008-09-01
期刊：
影响因子：
11.2
通讯作者：
Skorski T
中科院分区：
文献类型：
--
作者：
Cramer K;Nieborowska-Skorska M;Koptyra M;Slupianek A;Penserga ET;Eaves CJ;Aulitzky W;Skorski T
骨髓增殖性疾病(MPD)是一种干细胞来源的克隆性疾病，由c-abl、JAK2和PDGFR获得性异常引起，产生癌基因融合酪氨酸激酶(FTKs)，包括bcr/abl、TEL/ABL、TEL/JAK2和TEL/PDGFR。我们在这里展示了FTKs刺激在造血细胞系和慢性髓系白血病患者β+白血病干/祖细胞中的反应性氧物种(ROS)和DNA双链断裂(DSB)的形成。单链退火(SSA)是一种相对罕见但非常不忠诚的DSB修复机制，会导致染色体异常。利用整合到基因组DNA中的特定报告盒，我们发现BCR/ABL和其他FTK刺激SSA活性。伊马替尼介导的对bcr/abl的抑制取消了这一效应，暗示了一种激酶依赖的机制。具有伊马替尼抗性的bcr/abl突变株Y253F、E255K、T315I和H396P也可刺激SSA。未突变或突变的BCR/ABL激酶的表达增加，这是典型的急变期细胞和非常原始的慢性期CML细胞，与较高的SSA活性有关。BCR/ABL介导的SSA刺激伴随着RAD52和ERCC1核共定位的增强，RAD52和ERCC1在修复中起关键作用。综上所述，这些发现表明FTK通过产生DSB和刺激SSA修复来诱导染色体不稳定，从而在MPDS的疾病进展中发挥作用。
Myeloproliferative disorders (MPDs) are stem cell-derived clonal diseases arising as a consequence of acquired aberrations in c-ABL, JAK2, and PDGFR, that generate oncogenic fusion tyrosine kinases (FTKs) including BCR/ABL, TEL/ABL, TEL/JAK2, and TEL/PDGFβR. Here we show that FTKs stimulate the formation of reactive oxygen species (ROS) and DNA double-strand breaks (DSBs) both in hematopoietic cell lines and in CD34+ leukemic stem/progenitor cells from patients with chronic myeloid leukemia (CML). Single-strand annealing (SSA) represents a relatively rare, but very unfaithful DSB repair mechanism causing chromosomal aberrations. Using a specific reporter cassette integrated into genomic DNA, we found that BCR/ABL and other FTKs stimulated SSA activity. Imatinib-mediated inhibition of BCR/ABL abrogated this effect implicating a kinase-dependent mechanism. Y253F, E255K, T315I, and H396P mutants of BCR/ABL that confer imatinib resistance also stimulated SSA. Increased expression of either non-mutated or mutated BCR/ABL kinase, as is typical of blast phase cells and very primitive chronic phase CML cells, was associated with higher SSA activity. BCR/ABL-mediated stimulation of SSA was accompanied by enhanced nuclear co-localization of RAD52 and ERCC1, which play a key role in the repair. Taken together, these findings suggest a role of FTKs in causing disease progression in MPDs by inducing chromosomal instability through the production of DSBs and stimulation of SSA repair.