急性髓系白血病干细胞 (LSC) 的生存特别依赖于氧化磷酸化 (OXPHOS)。此外，OXPHOS 的维持依赖于 BCL-2，这为使用 BCL-2 抑制剂 Venetoclax 靶向 LSC 创造了治疗机会。虽然基于维奈托克的治疗方案已显示出有希望的临床活性，但耐药性的出现也很普遍。因此，在本研究中，我们研究了线粒体特性如何影响维奈托克反应性。我们的数据表明，药物反应性和非反应性 LSC 对线粒体钙的利用存在根本差异。相比之下，耐维奈托克的 LSC 表现出更活跃的代谢（即 OXPHOS）状态，钙水平相对较高。因此，我们测试了针对线粒体钙单向转运蛋白 MCU 的遗传和药理学方法。我们证明，抑制钙摄取可减少 OXPHOS 并导致根除 Venetoclax 耐药性 LSC。这些发现证明了钙信号在 LSC 中的核心作用，并为维奈托克耐药性的临床管理提供了途径。

Acute myeloid leukemia stem cells (LSCs) are uniquely reliant on oxidative phosphorylation (OXPHOS) for survival. Moreover, maintenance of OXPHOS is dependent on BCL-2, creating a therapeutic opportunity to target LSCs using the BCL-2 inhibitor venetoclax. While venetoclax-based regimens have shown promising clinical activity, the emergence of drug resistance is prevalent. Thus, in the present study, we investigated how mitochondrial properties may influence venetoclax responsiveness. Our data show that utilization of mitochondrial calcium is fundamentally different between drug-responsive and non-responsive LSCs. By comparison, venetoclax-resistant LSCs demonstrate a more active metabolic (i.e. OXPHOS) status with relatively high levels of calcium. Consequently, we tested genetic and pharmacological approaches to target the mitochondrial calcium uniporter, MCU. We demonstrate that inhibition of calcium uptake reduces OXPHOS and leads to eradication of venetoclax-resistant LSCs. These findings demonstrate a central role for calcium signaling in LSCs and provide an avenue for clinical management of venetoclax resistance.