A novel and highly effective mitochondrial uncoupling drug in T-cell leukemia

癌症研究 线粒体 白血病 背景(考古学) 下调和上调 生物 PI3K/AKT/mTOR通路 细胞生长 细胞生物学 细胞凋亡 免疫学 生物化学 基因 古生物学
作者
Victoria da Silva-Diz,Bin Cao,Olga Lancho,Eric Chiles,Amer Alasadi,Maya Aleksandrova,Shirley Luo,Amartya Singh,Hanlin Tao,David J. Augeri,Sonia Minuzzo,Stefano Indraccolo,Hossein Khiabanian,Xiaoyang Su,Shengkan Jin,Daniel Herranz
出处
期刊:Blood [American Society of Hematology]
卷期号:138 (15): 1317-1330 被引量:12
标识
DOI:10.1182/blood.2020008955
摘要

Abstract T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy. Despite recent advances in treatments with intensified chemotherapy regimens, relapse rates and associated morbidities remain high. In this context, metabolic dependencies have emerged as a druggable opportunity for the treatment of leukemia. Here, we tested the antileukemic effects of MB1-47, a newly developed mitochondrial uncoupling compound. MB1-47 treatment in T-ALL cells robustly inhibited cell proliferation via both cytostatic and cytotoxic effects as a result of compromised mitochondrial energy and metabolite depletion, which severely impaired nucleotide biosynthesis. Mechanistically, acute treatment with MB1-47 in primary leukemias promoted adenosine monophosphate–activated serine/threonine protein kinase (AMPK) activation and downregulation of mammalian target of rapamycin (mTOR) signaling, stalling anabolic pathways that support leukemic cell survival. Indeed, MB1-47 treatment in mice harboring either murine NOTCH1-induced primary leukemias or human T-ALL patient-derived xenografts (PDXs) led to potent antileukemic effects with a significant extension in survival without overlapping toxicities. Overall, our findings demonstrate a critical role for mitochondrial oxidative phosphorylation in T-ALL and uncover MB1-47–driven mitochondrial uncoupling as a novel therapeutic strategy for the treatment of this disease.
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