Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA.
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
J Exp Med. 2018 Dec 3;215(12):3094-3114. doi: 10.1084/jem.20180570. Epub 2018 Nov 7.
The tendency of mitochondria to undergo or resist BCL2-controlled apoptosis (so-called mitochondrial priming) is a powerful predictor of response to cytotoxic chemotherapy. Fully exploiting this finding will require unraveling the molecular genetics underlying phenotypic variability in mitochondrial priming. Here, we report that mitochondrial apoptosis resistance in T cell acute lymphoblastic leukemia (T-ALL) is mediated by inactivation of polycomb repressive complex 2 (PRC2). In T-ALL clinical specimens, loss-of-function mutations of PRC2 core components (, , or ) were associated with mitochondrial apoptosis resistance. In T-ALL cells, PRC2 depletion induced resistance to apoptosis induction by multiple chemotherapeutics with distinct mechanisms of action. PRC2 loss induced apoptosis resistance via transcriptional up-regulation of the LIM domain transcription factor and downstream up-regulation of the mitochondrial chaperone These findings demonstrate the importance of mitochondrial apoptotic priming as a prognostic factor in T-ALL and implicate mitochondrial chaperone function as a molecular determinant of chemotherapy response.
线粒体发生或抵抗 BCL2 控制的细胞凋亡（所谓的线粒体引发）的趋势是对细胞毒性化疗反应的有力预测指标。要充分利用这一发现，就需要阐明线粒体引发表型变异性的分子遗传学基础。在这里，我们报告称，T 细胞急性淋巴细胞白血病 (T-ALL) 中的线粒体抗凋亡是通过多梳抑制复合物 2 (PRC2) 的失活来介导的。在 T-ALL 临床标本中，PRC2 核心成分（、、或）的功能丧失突变与线粒体凋亡抵抗有关。在 T-ALL 细胞中，PRC2 的缺失诱导对多种具有不同作用机制的化疗药物诱导的细胞凋亡的抵抗。PRC2 的缺失通过 LIM 结构域转录因子和线粒体伴侣的转录上调诱导凋亡抵抗，而下调则通过线粒体伴侣的转录上调诱导凋亡抵抗。这些发现表明线粒体凋亡引发作为 T-ALL 中的预后因素的重要性，并暗示线粒体伴侣功能作为化疗反应的分子决定因素。
