Sheth Anagha Inguva, Engel Krysta, Tolison Hunter, Althoff Mark J, Amaya Maria L, Krug Anna, Young Tracy, Pei Shanshan, Patel Sweta B, Minhajuddin Mohammad, Winters Amanda, Miller Regan, Shelton Ian, St-Germain Jonathan, Ling Tianyi, Jones Courtney, Raught Brian, Gillen Austin, Ransom Monica, Staggs Sarah, Smith Clayton A, Pollyea Daniel A, Stevens Brett M, Jordan Craig T
Division of Hematology, University of Colorado School of Medicine, Aurora, CO, USA.
These authors contributed equally.
bioRxiv. 2023 Oct 3:2023.10.02.560330. doi: 10.1101/2023.10.02.560330.
We previously reported that acute myeloid leukemia stem cells (LSCs) are uniquely reliant on oxidative phosphorylation (OXPHOS) for survival. Moreover, maintenance of OXPHOS is dependent on BCL2, creating a therapeutic opportunity to target LSCs using the BCL2 inhibitor drug venetoclax. While venetoclax-based regimens have indeed shown promising clinical activity, the emergence of drug resistance is prevalent. Thus, in the present study, we investigated how mitochondrial properties may influence mechanisms that dictate 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 steady-state levels of calcium. Consequently, we tested genetic and pharmacological approaches to target the mitochondrial calcium uniporter, MCU. We demonstrate that inhibition of calcium uptake sharply reduces OXPHOS and leads to eradication of venetoclax-resistant LSCs. These findings demonstrate a central role for calcium signaling in the biology of LSCs and provide a therapeutic avenue for clinical management of venetoclax resistance.
我们之前报道过，急性髓系白血病干细胞（LSCs）在生存方面独特地依赖氧化磷酸化（OXPHOS）。此外，OXPHOS的维持依赖于BCL2，这为使用BCL2抑制剂药物维奈托克靶向LSCs创造了治疗机会。虽然基于维奈托克的治疗方案确实显示出了有前景的临床活性，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决定维奈托克反应性的机制。我们的数据表明，药物反应性和无反应性LSCs之间线粒体钙的利用存在根本差异。相比之下，对维奈托克耐药的LSCs表现出更活跃的代谢（即OXPHOS）状态，钙的稳态水平相对较高。因此，我们测试了针对线粒体钙单向转运体MCU的基因和药理学方法。我们证明，抑制钙摄取会大幅降低OXPHOS，并导致对维奈托克耐药的LSCs被根除。这些发现证明了钙信号在LSCs生物学中的核心作用，并为维奈托克耐药的临床管理提供了一条治疗途径。
