PMID- 33876224 OWN - NLM STAT- MEDLINE DCOM- 20211207 LR - 20221015 IS - 1528-0020 (Electronic) IS - 0006-4971 (Print) IS - 0006-4971 (Linking) VI - 138 IP - 15 DP - 2021 Oct 14 TI - A novel and highly effective mitochondrial uncoupling drug in T-cell leukemia. PG - 1317-1330 LID - 10.1182/blood.2020008955 [doi] AB - 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. CI - (c) 2021 by The American Society of Hematology. FAU - da Silva-Diz, Victoria AU - da Silva-Diz V AUID- ORCID: 0000-0002-1508-2999 AD - Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ. FAU - Cao, Bin AU - Cao B AD - Department of Medicinal Chemistry, School of Pharmacy, Rutgers University, Piscataway, NJ. FAU - Lancho, Olga AU - Lancho O AUID- ORCID: 0000-0001-5819-4715 AD - Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ. FAU - Chiles, Eric AU - Chiles E AUID- ORCID: 0000-0003-3354-607X AD - Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ. FAU - Alasadi, Amer AU - Alasadi A AUID- ORCID: 0000-0001-6082-1597 AD - Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ. FAU - Aleksandrova, Maya AU - Aleksandrova M AD - Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ. FAU - Luo, Shirley AU - Luo S AD - Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ. FAU - Singh, Amartya AU - Singh A AD - Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ. AD - Center for Systems and Computational Biology, Rutgers University, New Brunswick, NJ. FAU - Tao, Hanlin AU - Tao H AUID- ORCID: 0000-0003-0789-8311 AD - Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ. FAU - Augeri, David AU - Augeri D AD - Department of Medicinal Chemistry, School of Pharmacy, Rutgers University, Piscataway, NJ. FAU - Minuzzo, Sonia AU - Minuzzo S AD - Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy. FAU - Indraccolo, Stefano AU - Indraccolo S AD - Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy. AD - Basic and Translational Oncology Unit, Veneto Institute of Oncology-Scientific Institute for Research, Hospitalization and Healthcare (IOV-IRCCS), Padova, Italy. FAU - Khiabanian, Hossein AU - Khiabanian H AD - Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ. AD - Center for Systems and Computational Biology, Rutgers University, New Brunswick, NJ. AD - Department of Pathology and Laboratory Medicine, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ; and. FAU - Su, Xiaoyang AU - Su X AUID- ORCID: 0000-0001-8081-1396 AD - Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ. AD - Department of Medicine, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ. FAU - Jin, Shengkan AU - Jin S AUID- ORCID: 0000-0002-5979-7232 AD - Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ. FAU - Herranz, Daniel AU - Herranz D AUID- ORCID: 0000-0003-1768-5969 AD - Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ. AD - Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ. LA - eng GR - R00 CA197869/CA/NCI NIH HHS/United States GR - R01 CA236936/CA/NCI NIH HHS/United States GR - P30 CA072720/CA/NCI NIH HHS/United States GR - R21 CA216604/CA/NCI NIH HHS/United States GR - R21 AA027050/AA/NIAAA NIH HHS/United States GR - R01 CA233662/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - United States TA - Blood JT - Blood JID - 7603509 RN - 0 (Antineoplastic Agents) RN - 0 (Uncoupling Agents) SB - IM MH - Animals MH - Antineoplastic Agents/pharmacology/*therapeutic use MH - Cell Line, Tumor MH - Cell Proliferation/drug effects MH - Humans MH - Mice MH - Mitochondria/*drug effects/metabolism MH - Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/*drug therapy/metabolism MH - Uncoupling Agents/pharmacology/*therapeutic use PMC - PMC8525334 EDAT- 2021/04/21 06:00 MHDA- 2021/12/15 06:00 PMCR- 2022/10/14 CRDT- 2021/04/20 06:39 PHST- 2020/09/01 00:00 [received] PHST- 2021/03/31 00:00 [accepted] PHST- 2021/04/21 06:00 [pubmed] PHST- 2021/12/15 06:00 [medline] PHST- 2021/04/20 06:39 [entrez] PHST- 2022/10/14 00:00 [pmc-release] AID - S0006-4971(21)00891-0 [pii] AID - 2021/BLD2020008955 [pii] AID - 10.1182/blood.2020008955 [doi] PST - ppublish SO - Blood. 2021 Oct 14;138(15):1317-1330. doi: 10.1182/blood.2020008955.