Mitochondrial BAX Determines the Predisposition to Apoptosis in Human AML
Mitochondrial BAX Determines the Predisposition to Apoptosis in Human AML
复制标题
DOI：
10.1158/1078-0432.ccr-16-1941
复制
发表时间：
2017-08-15
影响因子：
11.5
通讯作者：
Edlich, Frank
中科院分区：
文献类型：
--
作者：
Reichenbach, Frank;Wiedenmann, Cornelius;Edlich, Frank
目的：细胞凋亡信号传导的细胞间变异性有助于临床异质性瘤形成（如急性髓性白血病（AML））对细胞毒性应激的异质性反应。BCL-2蛋白BAX和巴克可以使哺乳动物细胞凋亡，并通过从线粒体到胞质溶胶的逆转位而被抑制。BAX和巴克的亚细胞定位可以确定细胞倾向于凋亡death.Experimental Design：BAX和巴克的相对定位通过AML细胞系和患者样本的测试队列和验证队列的分级来确定。人AML显示出令人惊讶的多种相对BAX定位。在48名AML患者的测试队列中，线粒体移位的BAX与患者生存率、FLT 3-ITD状态和白细胞增多症的改善相关。对80例接受骨髓抑制化疗的老年患者的验证队列分析证实，BAX相对定位与疾病进展的可能性、FLT 3-ITD状态和白细胞增多相关。因此，相对BAX定位可能有助于确定老年或体弱患者谁可能受益于细胞毒性therapeutic.Conclusions：在这两个独立的AML队列的回顾性分析，我们的数据表明，Bax定位可以预测AML患者的预后和细胞凋亡倾向，结合已知和未知因素的实际贡献，最终的“共同路径”。“（C）2017年AACR。
Purpose: Cell-to-cell variability in apoptosis signaling contributes to heterogenic responses to cytotoxic stress in clinically heterogeneous neoplasia, such as acute myeloid leukemia (AML). The BCL-2 proteins BAX and BAK can commit mammalian cells to apoptosis and are inhibited by retrotranslocation from the mitochondria into the cytosol. The subcellular localization of BAX and BAK could determine the cellular predisposition to apoptotic death.Experimental Design: The relative localization of BAX and BAK was determined by fractionation of AML cell lines and patient samples of a test cohort and a validation cohort.Results: This study shows that relative BAX localization determines the predisposition of different AML cell lines to apoptosis. Human AML displays a surprising variety of relative BAX localizations. In a test cohort of 48 patients with AML, mitochondriashifted BAX correlated with improved patient survival, FLT3-ITD status, and leukocytosis. Analysis of a validation cohort of 80 elderly patients treated with myelosuppressive chemotherapy confirmed that relative BAX localization correlates with probability of disease progression, FLT3-ITD status, and leukocytosis. Relative BAX localization could therefore be helpful to identify elderly or frail patients who may benefit from cytotoxic therapy.Conclusions: In this retrospective analysis of two independent AML cohorts, our data suggest that Bax localization may predict prognosis of patients with AML and cellular predisposition to apoptosis, combining the actual contribution of known and unknown factors to a final "common path." (C) 2017 AACR.