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

Baran N, Lodi A, Dhungana Y, Herbrich S, Collins M, Sweeney S, Pandey R, Skwarska A, Patel S, Tremblay M, Kuruvilla VM, Cavazos A, Kaplan M, Warmoes MO, Veiga DT, Furudate K, Rojas-Sutterin S, Haman A, Gareau Y, Marinier A, Ma H, Harutyunyan K, Daher M, Garcia LM, Al-Atrash G, Piya S, Ruvolo V, Yang W, Shanmugavelandy SS, Feng N, Gay J, Du D, Yang JJ, Hoff FW, Kaminski M, Tomczak K, Eric Davis R, Herranz D, Ferrando A, Jabbour EJ, Emilia Di Francesco M, Teachey DT, Horton TM, Kornblau S, Rezvani K, Sauvageau G, Gagea M, Andreeff M, Takahashi K, Marszalek JR, Lorenzi PL, Yu J, Tiziani S, Hoang T, Konopleva M

Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

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.

Nat Commun 2022;13(1):2801.

Pubmed ID: 35589701

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