Targeting Acute Myeloid Leukemia Stem Cells through Perturbation of Mitochondrial Calcium.

IF 29.7 1区 医学 Q1 ONCOLOGY
Anagha Inguva Sheth, Mark J Althoff, Hunter Tolison, Krysta Engel, Maria L Amaya, Anna E Krug, Tracy N Young, Mohammad Minhajuddin, Shanshan Pei, Sweta B Patel, Amanda Winters, Regan Miller, Ian T Shelton, Jonathan St-Germain, Tianyi Ling, Courtney L Jones, Brian Raught, Austin E Gillen, Monica Ransom, Sarah Staggs, Clayton A Smith, Daniel A Pollyea, Brett M Stevens, Craig T Jordan
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引用次数: 0

Abstract

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.

通过干扰线粒体钙来靶向急性髓性白血病干细胞
急性髓性白血病干细胞(LSCs)的生存独特地依赖于氧化磷酸化(OXPHOS)。此外,OXPHOS的维持依赖于BCL-2,这为使用BCL-2抑制剂venetoclax靶向LSCs创造了治疗机会。虽然以 venetoclax 为基础的治疗方案已显示出良好的临床活性,但耐药性的出现却十分普遍。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。我们的数据显示,对药物有反应的 LSCs 和无反应的 LSCs 对线粒体钙的利用有本质区别。相比之下,耐药 LSCs 的代谢(即 OXPHOS)状态更活跃,钙含量相对较高。因此,我们测试了针对线粒体钙离子通道 MCU 的基因和药理学方法。我们证明,抑制钙的摄取会降低 OXPHOS,从而根除对 venetoclax 耐药的 LSCs。这些发现证明了钙信号在LSCs中的核心作用,并为Venetoclax耐药的临床治疗提供了一条途径。
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来源期刊
Cancer discovery
Cancer discovery ONCOLOGY-
CiteScore
22.90
自引率
1.40%
发文量
838
审稿时长
6-12 weeks
期刊介绍: Cancer Discovery publishes high-impact, peer-reviewed articles detailing significant advances in both research and clinical trials. Serving as a premier cancer information resource, the journal also features Review Articles, Perspectives, Commentaries, News stories, and Research Watch summaries to keep readers abreast of the latest findings in the field. Covering a wide range of topics, from laboratory research to clinical trials and epidemiologic studies, Cancer Discovery spans the entire spectrum of cancer research and medicine.
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