ABT-737 increases tyrosine kinase inhibitor-induced apoptosis in chronic myeloid leukemia cells through XIAP downregulation and sensitizes CD34+ CD38- population to imatinib
ABT-737 increases tyrosine kinase inhibitor-induced apoptosis in chronic myeloid leukemia cells through XIAP downregulation and sensitizes CD34+ CD38- population to imatinib
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DOI：
10.1016/j.exphem.2012.01.004
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发表时间：
2012-05-01
影响因子：
2.6
通讯作者：
Belloc, Francis
中科院分区：
文献类型：
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作者：
Airiau, Kelly;Mahon, Francois-Xavier;Belloc, Francis
慢性粒细胞白血病（CML）的致瘤性是由致癌的BCR-ABL酪氨酸激酶驱动的。特异性酪氨酸激酶抑制剂（TKI）已被设计出来，目前用于治疗CML。这些TKI以BIM依赖性机制诱导白血病细胞凋亡。我们假设BIM活性的增加可以使CML细胞对TKI敏感。我们通过使用Bcl-2和Bcl-XL抑制剂ABT-737来阻断Bcl-2家族的抗凋亡蛋白。ABT-737将Bcl-2蛋白相互作用修饰为促凋亡表型。它与TKI的组合在CML细胞系中产生了强烈的协同作用。这种关联还诱导了X连锁细胞凋亡抑制因子（XIAP）的大量减少，随后是caspase-3的激活。这种XIAP降低是由于翻译后事件。线粒体丝氨酸蛋白酶HtrA 2/Omi被鉴定为负责这种脱靶效应。然后，ABT-737和TKI在多个水平上协同诱导CML细胞系的凋亡，并且在CML造血祖细胞中也观察到这种联合的益处。有趣的是，在更不成熟的CD 34（+）CD 38（-）TKI不敏感人群中也观察到致死效应。联合治疗可能是治疗CML患者的一个有趣的策略。(C)2012 ISEH -血液学和干细胞学会。爱思唯尔公司出版
Chronic myeloid leukemia (CML) tumorigenicity is driven by the oncogenic BCR-ABL tyrosine kinase. Specific tyrosine kinase inhibitors (TKI) have been designed and are now used for the treatment of CML. These TKI induce apoptosis in leukemic cells in a BIM-dependent mechanism. We hypothesized that an increase in BIM activity could sensitize CML cells to TKI. We blocked the anti-apoptotic proteins of the Bcl-2 family by using ABT-737, a Bcl-2 and Bcl-XL inhibitor. ABT-737 modified Bcl-2 protein interactions toward a pro-apoptotic phenotype. Its combination with TKI resulted in a strong synergism in CML cell lines. The association also induced a large decrease in X-linked inhibitor of apoptosis (XIAP), followed by caspase-3 activation. This XIAP decrease was due to post-translational events. The mitochondrial serine protease HtrA2/Omi was identified as being responsible for this off-target effect. Then, ABT-737 and TKI cooperate at several levels to induce apoptosis of CML cells lines, and the benefit of this association was also observed in CML hematopoietic progenitors. Interestingly, a lethal effect was also observed in the more immature CD34(+)CD38(-) TKI-insensitive population. Combination therapy might by an interesting strategy for the treatment of CML patients. (C) 2012 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc.