Selective BCL-2 inhibition by ABT-199 causes on-target cell death in acute myeloid leukemia.
Selective BCL-2 inhibition by ABT-199 causes on-target cell death in acute myeloid leukemia.
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DOI：
10.1158/2159-8290.cd-13-0609
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发表时间：
2014-03
期刊：
影响因子：
28.2
通讯作者：
Letai AG
中科院分区：
文献类型：
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作者：
Pan R;Hogdal LJ;Benito JM;Bucci D;Han L;Borthakur G;Cortes J;DeAngelo DJ;Debose L;Mu H;Döhner H;Gaidzik VI;Galinsky I;Golfman LS;Haferlach T;Harutyunyan KG;Hu J;Leverson JD;Marcucci G;Müschen M;Newman R;Park E;Ruvolo PP;Ruvolo V;Ryan J;Schindela S;Zweidler-McKay P;Stone RM;Kantarjian H;Andreeff M;Konopleva M;Letai AG
b细胞白血病/淋巴瘤2 （BCL-2）阻止线粒体的程序性细胞死亡。确定抑制BCL-2治疗效果最好的肿瘤仍然是一个挑战。在这里，我们证明急性髓性白血病（AML）细胞系、原发患者样本和小鼠原发异种移植物对选择性BCL-2拮抗剂ABT-199治疗非常敏感。在原代患者细胞中，中位IC50约为10 nM，细胞在2小时内死亡。我们的体外敏感性结果与观察到的慢性淋巴细胞白血病（CLL）比较有利，慢性淋巴细胞白血病是ABT-199在临床试验中表现出一致的活性。此外，利用BH3谱分析的线粒体研究表明，线粒体活性与细胞毒性密切相关，支持非靶线粒体作用机制。我们的蛋白质和BH3分析研究提供了有前途的工具，可以作为ABT-199在AML临床试验中的预测性生物标志物进行测试。
B-cell leukemia/lymphoma 2 (BCL-2) prevents commitment to programmed cell death at the mitochondrion. It remains a challenge to identify those tumors that are best treated by inhibition of BCL-2. Here we demonstrate that acute myeloid leukemia (AML) cell lines, primary patient samples, and murine primary xenografts are very sensitive to treatment with the selective BCL-2 antagonist ABT-199. In primary patient cells, the median IC50 was approximately 10 nM, and cell death occurred within 2 h. Our ex vivo sensitivity results compare favorably with those observed for chronic lymphocytic leukemia (CLL), a disease for which ABT-199 has demonstrated consistent activity in clinical trials. Moreover, mitochondrial studies using BH3 profiling demonstrate activity at the mitochondrion that correlates well with cytotoxicity, supporting an on target mitochondrial mechanism of action. Our protein and BH3 profiling studies provide promising tools that can be tested as predictive biomarkers in any clinical trial of ABT-199 in AML.