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首页> 外文期刊>Molecular and Cellular Biology >Fusion Tyrosine Kinases Induce Drug Resistance by Stimulation of Homology-Dependent Recombination Repair, Prolongation of G2/M Phase, and Protection from Apoptosis
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Fusion Tyrosine Kinases Induce Drug Resistance by Stimulation of Homology-Dependent Recombination Repair, Prolongation of G2/M Phase, and Protection from Apoptosis

机译：融合酪氨酸激酶通过刺激依赖同源性的重组修复，延长G2 / M期并防止细胞凋亡来诱导耐药性。

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Fusion tyrosine kinases (FTKs) such as BCR/ABL, TEL/ABL, TEL/JAK2, TEL/PDGFβR, TEL/TRKC(L), and NPM/ALK arise from reciprocal chromosomal translocations and cause acute and chronic leukemias and non-Hodgkin's lymphoma. FTK-transformed cells displayed drug resistance against the cytostatic drugs cisplatin and mitomycin C. These cells were not protected from drug-mediated DNA damage, implicating activation of the mechanisms preventing DNA damage-induced apoptosis. Various FTKs, except TEL/TRKC(L), can activate STAT5, which may be required to induce drug resistance. We show that STAT5 is essential for FTK-dependent upregulation of RAD51, which plays a central role in homology-dependent recombinational repair (HRR) of DNA double-strand breaks (DSBs). Elevated levels of Rad51 contributed to the induction of drug resistance and facilitation of the HRR in FTK-transformed cells. In addition, expression of antiapoptotic protein Bcl-xL was enhanced in cells transformed by the FTKs able to activate STAT5. Moreover, cells transformed by all examined FTKs displayed G2/M delay upon drug treatment. Individually, elevated levels of Rad51, Bcl-xL, or G2/M delay were responsible for induction of a modest drug resistance. Interestingly, combination of these three factors in nontransformed cells induced drug resistance of a magnitude similar to that observed in cells expressing FTKs activating STAT5. Thus, we postulate that RAD51-dependent facilitation of DSB repair, antiapoptotic activity of Bcl-xL, and delay in progression through the G2/M phase work in concert to induce drug resistance in FTK-positive leukemias and lymphomas.
机译：融合酪氨酸激酶（FTK），例如BCR / ABL，TEL / ABL，TEL / JAK2，TEL /PDGFβR，TEL / TRKC（L）和NPM / ALK产生于相互的染色体易位，并引起急性和慢性白血病以及非何杰金氏病淋巴瘤。 FTK转化的细胞显示出对细胞生长抑制药顺铂和丝裂霉素C的耐药性。这些细胞未受到药物介导的DNA损伤的保护，暗示了防止DNA损伤诱导的细胞凋亡的机制的激活。除TEL / TRKC（L）外，其他各种FTK均可激活STAT5，这可能是诱导耐药性所必需的。我们显示STAT5对于 RAD51 的FTK依赖性上调是必不可少的，它在DNA双链断裂（DSBs）的同源性依赖性重组修复（HRR）中起着核心作用。 Rad51的水平升高有助于在FTK转化的细胞中诱导耐药性并促进HRR。另外，在由能够激活STAT5的FTKs转化的细胞中，抗​​凋亡蛋白Bcl-xL的表达增强了。此外，经所有检查的FTKs转化的细胞在药物治疗后显示出G 2 / M延迟。单独地，Rad51，Bcl-xL或G 2 / M延迟水平升高是引起中等耐药性的原因。有趣的是，这三种因素在未转化细胞中的结合诱导的耐药性与在表达激活STAT5的FTK的细胞中观察到的相似。因此，我们推测，RAD51依赖的DSB修复促进，Bcl-xL的抗凋亡活性以及通过G 2 / M期的进展延迟协同作用可诱导FTK阳性白血病的耐药性和淋巴瘤。

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