Inhibition of mitochondrial complex I reverses NOTCH1-driven metabolic reprogramming in T-cell acute lymphoblastic leukemia.

Autor: Baran N; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Lodi A; Department of Nutritional Sciences, Dell Pediatric Research Institute, Dell Medical School, The University of Texas at Austin, Austin, TX, USA., Dhungana Y; St. Jude Graduate School of Biomedical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA., Herbrich S; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Collins M; Department of Nutritional Sciences, Dell Pediatric Research Institute, Dell Medical School, The University of Texas at Austin, Austin, TX, USA., Sweeney S; Department of Nutritional Sciences, Dell Pediatric Research Institute, Dell Medical School, The University of Texas at Austin, Austin, TX, USA., Pandey R; Department of Nutritional Sciences, Dell Pediatric Research Institute, Dell Medical School, The University of Texas at Austin, Austin, TX, USA., Skwarska A; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Patel S; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Tremblay M; Institute for Research in Immunology and Cancer, The University of Montreal, Montréal, QC, Canada., Kuruvilla VM; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Cavazos A; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Kaplan M; Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Warmoes MO; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Veiga DT; The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA., Furudate K; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Department of Oral and Maxillofacial Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori, Japan., Rojas-Sutterin S; Institute for Research in Immunology and Cancer, The University of Montreal, Montréal, QC, Canada., Haman A; Institute for Research in Immunology and Cancer, The University of Montreal, Montréal, QC, Canada., Gareau Y; Institute for Research in Immunology and Cancer, The University of Montreal, Montréal, QC, Canada., Marinier A; Institute for Research in Immunology and Cancer, The University of Montreal, Montréal, QC, Canada., Ma H; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Harutyunyan K; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Daher M; Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Garcia LM; Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Al-Atrash G; Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Piya S; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Ruvolo V; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Yang W; Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA., Shanmugavelandy SS; Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Feng N; TRACTION Platform, Therapeutics Discovery Division, University of Texas M. D. Anderson Cancer Center, Houston, USA., Gay J; TRACTION Platform, Therapeutics Discovery Division, University of Texas M. D. Anderson Cancer Center, Houston, USA., Du D; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Yang JJ; Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA., Hoff FW; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Kaminski M; Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA., Tomczak K; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Eric Davis R; Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Herranz D; Rutgers Robert Wood Johnson Medical School, Cancer Institute of New Jersey, New Brunswick, NJ, USA., Ferrando A; Irving Cancer Research Center, Columbia University Irving Medical Center, New York, NY, USA., Jabbour EJ; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Emilia Di Francesco M; Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Teachey DT; Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA, USA., Horton TM; Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX, USA., Kornblau S; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Rezvani K; Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Sauvageau G; Institute for Research in Immunology and Cancer, The University of Montreal, Montréal, QC, Canada., Gagea M; Department of Veterinary Medicine and Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Andreeff M; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Takahashi K; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Marszalek JR; TRACTION Platform, Therapeutics Discovery Division, University of Texas M. D. Anderson Cancer Center, Houston, USA., Lorenzi PL; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Yu J; Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA., Tiziani S; Department of Nutritional Sciences, Dell Pediatric Research Institute, Dell Medical School, The University of Texas at Austin, Austin, TX, USA., Hoang T; Institute for Research in Immunology and Cancer, The University of Montreal, Montréal, QC, Canada.; Department of Pharmacology and Physiology, Faculty of Medicine, University of Montreal, Montreal, QC, Canada., Konopleva M; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. mkonople@mdanderson.org.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2022 May 19; Vol. 13 (1), pp. 2801. Date of Electronic Publication: 2022 May 19.
DOI: 10.1038/s41467-022-30396-3
Abstrakt: T-cell acute lymphoblastic leukemia (T-ALL) is commonly driven by activating mutations in NOTCH1 that facilitate glutamine oxidation. Here we identify oxidative phosphorylation (OxPhos) as a critical pathway for leukemia cell survival and demonstrate a direct relationship between NOTCH1, elevated OxPhos gene expression, and acquired chemoresistance in pre-leukemic and leukemic models. Disrupting OxPhos with IACS-010759, an inhibitor of mitochondrial complex I, causes potent growth inhibition through induction of metabolic shut-down and redox imbalance in NOTCH1-mutated and less so in NOTCH1-wt T-ALL cells. Mechanistically, inhibition of OxPhos induces a metabolic reprogramming into glutaminolysis. We show that pharmacological blockade of OxPhos combined with inducible knock-down of glutaminase, the key glutamine enzyme, confers synthetic lethality in mice harboring NOTCH1-mutated T-ALL. We leverage on this synthetic lethal interaction to demonstrate that IACS-010759 in combination with chemotherapy containing L-asparaginase, an enzyme that uncovers the glutamine dependency of leukemic cells, causes reduced glutaminolysis and profound tumor reduction in pre-clinical models of human T-ALL. In summary, this metabolic dependency of T-ALL on OxPhos provides a rational therapeutic target.
(© 2022. The Author(s).)
Databáze: MEDLINE
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