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

Victoria da Silva-Diz, Bin Cao, Olga Lancho, Eric Chiles, Amer Alasadi, Maya Aleksandrova, Shirley Luo, Amartya Singh, Hanlin Tao, David Augeri, Sonia Minuzzo, Stefano Indraccolo, Hossein Khiabanian, Xiaoyang Su, Shengkan Jin, Daniel Herranz

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1317-1330
Number of pages14
JournalBlood
Volume138
Issue number15
DOIs
StatePublished - Oct 14 2021

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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