Animals, Electron Transport Complex I, Glutamine, Mice, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Receptor, Notch1, T-Lymphocytes
Nat Commun 2022 May 19; 13(1):3801
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.
Baran, Natalia; Lodi, Alessia; Dhungana, Yogesh; Herbrich, Shelley; Collins, Meghan; Sweeney, Shannon; Pandey, Renu; Skwarska, Anna; Patel, Shraddha; Tremblay, Mathieu; Kuruvilla, Vinitha Mary; Cavazos, Antonio; Kaplan, Mecit; Warmoes, Marc O; Veiga, Diogo Troggian; Furudate, Ken; Rojas-Sutterin, Shanti; Haman, Andre; Gareau, Yves; Marinier, Anne; Ma, Helen; Harutyunyan, Karine; Daher, May; Garcia, Luciana Melo; Al-Atrash, Gheath; Piya, Sujan; Ruvolo, Vivian; Yang, Wentao; Shanmugavelandy, Sriram Saravanan; Feng, Ningping; Gay, Jason; Du, Di; Yang, Jun J; Hoff, Fieke W; Kaminski, Marcin; Tomczak, Katarzyna; Eric Davis, R; Herranz, Daniel; Ferrando, Adolfo; Jabbour, Elias J; Emilia Di Francesco, M; Teachey, David T; Horton, Terzah M; Kornblau, Steven; Rezvani, Katayoun; Sauvageau, Guy; Gagea, Mihai; Andreeff, Michael; Takahashi, Koichi; Marszalek, Joseph R; Lorenzi, Philip L; Yu, Jiyang; Tiziani, Stefano; Hoang, Trang; and Konopleva, Marina, "Inhibition of mitochondrial complex I reverses NOTCH1-driven metabolic reprogramming in T-cell acute lymphoblastic leukemia." (2022). Faculty Research 2022. 92.