Division of Hematology, University of Colorado School of Medicine, Aurora, Colorado.
Bone Marrow Transplantation Center of The First Affiliated Hospital & Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, China.
Cancer Discov. 2024 Oct 4;14(10):1922-1939. doi: 10.1158/2159-8290.CD-23-1145.
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. Although 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 nonresponsive LSCs. By comparison, venetoclax-resistant LSCs demonstrate an 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. 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. Significance: We identify increased utilization of mitochondrial calcium as a distinct metabolic requirement of venetoclax-resistant LSCs and demonstrate the potential of targeting mitochondrial calcium uptake as a therapeutic strategy.
急性髓系白血病干细胞（LSCs）对氧化磷酸化（OXPHOS）的依赖性是独特的，以维持生存。此外，OXPHOS 的维持依赖于 BCL-2，这为使用 BCL-2 抑制剂 venetoclax 靶向 LSCs 提供了一个治疗机会。尽管基于 venetoclax 的方案显示出有希望的临床活性，但耐药性的出现很普遍。因此，在本研究中，我们研究了线粒体特性如何影响 venetoclax 的反应性。我们的数据表明，药物反应性和非反应性 LSCs 之间的线粒体钙利用存在根本差异。相比之下，venetoclax 耐药的 LSCs 表现出活跃的代谢（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的遗传和药理学方法。我们证明抑制钙摄取可降低 OXPHOS 并导致 venetoclax 耐药的 LSCs 根除。这些发现表明钙信号在 LSCs 中起核心作用，并为 venetoclax 耐药的临床管理提供了一种途径。意义：我们确定增加线粒体钙的利用是 venetoclax 耐药 LSCs 的独特代谢需求，并证明靶向线粒体钙摄取作为一种治疗策略的潜力。
