Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia
Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia
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DOI：
10.1016/j.ccr.2006.10.006
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发表时间：
2006-11-01
期刊：
影响因子：
50.3
通讯作者：
Andreeff, Michael
中科院分区：
文献类型：
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作者：
Konopleva, Marina;Contractor, Rooha;Andreeff, Michael
BCL-2蛋白对细胞存活至关重要，并且在许多肿瘤中过表达。ABT-737是一种小分子BH 3模拟物，在临床前研究中显示出抗淋巴瘤和小细胞肺癌的单药活性。我们在这里报告，ABT-737有效地杀死急性髓系白血病原始细胞，祖细胞和干细胞，而不影响正常的造血细胞。ABT-737诱导BCL-2/BAX复合物的破坏和BAK依赖但BIM独立的内在凋亡途径的激活。在BCL-2磷酸化或MCL-1增加的细胞中，ABT-737无活性。抑制BCL-2磷酸化和减少MCL-1表达恢复对ABT-737的敏感性。这些数据表明，ABT-737可能是一个非常有效的抗白血病药物时，耐药机制在这里确定的考虑。
BCL-2 proteins are critical for cell survival and are overexpressed in many tumors. ABT-737 is a small-molecule BH3 mimetic that exhibits single-agent activity against lymphoma and small-cell lung cancer in preclinical studies. We here report that ABT-737 effectively kills acute myeloid leukemia blast, progenitor, and stem cells without affecting normal hematopoietic cells. ABT-737 induced the disruption of the BCL-2/BAX complex and BAK-dependent but BIM-independent activation of the intrinsic apoptotic pathway. In cells with phosphorylated BCL-2 or increased MCL-1, ABT-737 was inactive. Inhibition of BCL-2 phosphorylation and reduction of MCL-1 expression restored sensitivity to ABT-737. These data suggest that ABT-737 could be a highly effective antileukemia agent when the mechanisms of resistance identified here are considered.