Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Cell. 2012 Oct 12;151(2):344-55. doi: 10.1016/j.cell.2012.08.038.
Despite decades of successful use of cytotoxic chemotherapy in acute myelogenous leukemia (AML), the biological basis for its differential success among individuals and for the existence of a therapeutic index has remained obscure. Rather than taking a genetic approach favored by many, we took a functional approach to ask how differential mitochondrial readiness for apoptosis ("priming") might explain individual variation in clinical behavior. We found that mitochondrial priming measured by BH3 profiling was a determinant of initial response to induction chemotherapy, relapse after remission, and requirement for allogeneic bone marrow transplantation. Differential priming between malignant myeloblasts and normal hematopoietic stem cells supports a mitochondrial basis to the therapeutic index for chemotherapy. BH3 profiling identified BCL-2 inhibition as a targeted strategy likely to have a useful therapeutic index. BH3 profiling refines predictive information provided by conventional biomarkers currently in use and thus may itself have utility as a clinical predictive biomarker. PAPERCLIP:
尽管细胞毒性化疗在急性髓系白血病（AML）中的应用已经成功了几十年，但它在个体中的不同疗效和治疗指数的存在的生物学基础仍然不清楚。我们没有采用许多人青睐的遗传方法，而是采用了一种功能方法，来研究细胞凋亡（“引发”）的线粒体准备状态的差异如何解释临床行为的个体差异。我们发现，通过 BH3 分析测量的线粒体引发是诱导化疗初始反应、缓解后复发以及异体骨髓移植需求的决定因素。恶性髓样白血病细胞和正常造血干细胞之间的差异引发支持化疗治疗指数的线粒体基础。BH3 分析确定 BCL-2 抑制是一种可能具有有用治疗指数的靶向策略。BH3 分析细化了目前使用的常规生物标志物提供的预测信息，因此本身可能作为一种临床预测生物标志物具有实用性。
