The BCL-2 Inhibitor Venetoclax in Combination with Azacitidine Disrupts Energy Metabolism and Targets Leukemia Stem Cells in Acute Myeloid Leukemia Patients

The manuscript summarizes clinical and laboratory-based evaluation of 33 AML patients treated with a novel drug combination, venetoclax and azacytidine. Our findings indicate that this regimen is exceptionally promising for the treatment of de novo AML patients. The improvement in outcomes in comparison to conventional therapy is quite remarkable. The manuscript explores the mechanistic basis for the clinical outcomes, testing the hypothesis that venetoclax and azacytidine effectively target leukemia stem cells (LSCs) in vivo. Our findings indicate the regimen is highly active towards the LSC population. Specifically, we describe a mechanism that suppresses the activity of electron transport complex II, resulting in inhibition of oxidative phosphorylation. Overall design: Respective populations were sorted from human bone marrow mononuclear cells after patients received venetoclax and azacitidine for 6 hours (pre drug time 0 collected and post drug 6 hr labelled accordingly), after staining with CellRox dye and sorting the lowest 20% of the blasts staining for CellROX.本手稿总结了33例接受新型联合药物方案（维奈克拉（venetoclax）与阿扎胞苷（azacytidine））治疗的急性髓系白血病（AML, Acute Myeloid Leukemia）患者的临床与实验室评估结果。研究结果表明，该治疗方案对于初诊急性髓系白血病患者具有极具前景的治疗潜力。相较于传统疗法，该方案在治疗结局上的改善效果极为显著。本手稿还探讨了该临床疗效背后的机制基础，验证了“维奈克拉与阿扎胞苷可在体内有效靶向白血病干细胞（LSCs）”这一假说，研究结果显示该方案对白血病干细胞群体具有高度活性。具体而言，本研究阐明了一种可抑制电子传递复合物II活性、进而阻断氧化磷酸化的作用机制。整体实验设计：分别在患者接受维奈克拉与阿扎胞苷治疗6小时后，从其骨髓单个核细胞中分选目标细胞群（分别收集给药前0小时样本与给药后6小时样本并进行相应标记）；随后使用CellRox染料进行染色，分选其中CellRox染色强度最低的20%白血病母细胞群体。