Imatinib sensitivity in BCR-ABL1-positive chronic myeloid leukemia cells is regulated by the remaining normal ABL1 allele.
Imatinib sensitivity in BCR-ABL1-positive chronic myeloid leukemia cells is regulated by the remaining normal ABL1 allele.
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BCR-ABL1 阳性慢性粒细胞白血病细胞中的伊马替尼敏感性由剩余的正常 ABL1 等位基因调节。
DOI：
10.1158/0008-5472.can-11-0068
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发表时间：
2011
期刊：
影响因子：
11.2
通讯作者：
Skorski,Tomasz
中科院分区：
文献类型：
--
作者：
Virgili,Anna;Koptyra,Mateusz;Dasgupta,Yashodhara;Glodkowska-Mrowka,Eliza;Stoklosa,Tomasz;Nacheva,ElisabethP;Skorski,Tomasz
携带致癌基因BCR-ABL1和正常ABL1等位基因的慢性粒细胞白血病慢性期(CML-CP)细胞通常对ABL1激酶抑制剂伊马替尼产生抗药性。在这里，我们报告了在这些肿瘤中剩余的正常ABL1等位基因的丢失，这是由于在治疗期间没有实现完全细胞遗传学缓解(CCyR)的患者的9q34隐蔽间质缺失导致的，产生了一种新的意想不到的伊马替尼耐药机制。Bcr-abl1阳性−/−白血病细胞对伊马替尼耐药，表现为持续的bcr-abl1介导的酪氨酸磷酸化，缺乏bcr-abl1蛋白降解，细胞存活率和克隆形成活性增加。在abl1阴性的慢性粒细胞白血病细胞和bcr-abl1阳性的−/−小鼠白血病细胞中，表达abl1激酶，而不是激酶死亡突变体，恢复了伊马替尼的抗白血病作用。虽然参与bcr-abl1降解的蛋白在ABL1−/−细胞中表达下调，但伊马替尼的细胞内浓度及其转运体的表达并未受到影响。此外，在ABL1−/−白血病中，与伊马替尼耐药相关的12个基因被有利地解除调控。综上所述，我们的结果表明，正常ABL1激酶的丢失可能是对CML治疗结果产生重大影响的关键预后因素。癌症资源；71(16)；5381-6。
Chronic myeloid leukemia in chronic phase (CML-CP) cells that harbor oncogenicBCR-ABL1and normalABL1allele often become resistant to the ABL1 kinase inhibitor imatinib. Here, we report that loss of the remaining normalABL1allele in these tumors, which results from cryptic interstitial deletion in 9q34 in patients who did not achieve a complete cytogenetic remission (CCyR) during treatment, engenders a novel unexpected mechanism of imatinib resistance. BCR-ABL1–positiveAbl1−/−leukemia cells were refractory to imatinib as indicated by persistent BCR-ABL1–mediated tyrosine phosphorylation, lack of BCR-ABL1 protein degradation, increased cell survival, and clonogenic activity. Expression of ABL1 kinase, but not a kinase-dead mutant, restored the antileukemic effects of imatinib in ABL1-negative chronic myelogenous leukemia (CML) cells and in BCR-ABL1–positiveAbl1−/−murine leukemia cells. The intracellular concentration of imatinib and expression of its transporters were not affected, although proteins involved in BCR-ABL1 degradation were downregulated inAbl1−/−cells. Furthermore, 12 genes associated with imatinib resistance were favorably deregulated inAbl1−/−leukemia. Taken together, our results indicate that loss of the normal ABL1 kinase may serve as a key prognostic factor that exerts major impact on CML treatment outcomes.Cancer Res; 71(16); 5381–6. ©2011 AACR.