TY - JOUR
T1 - Inhibition of mitochondrial complex I reverses NOTCH1-driven metabolic reprogramming in T-cell acute lymphoblastic leukemia
AU - Baran, Natalia
AU - Lodi, Alessia
AU - Dhungana, Yogesh
AU - Herbrich, Shelley
AU - Collins, Meghan
AU - Sweeney, Shannon
AU - Pandey, Renu
AU - Skwarska, Anna
AU - Patel, Shraddha
AU - Tremblay, Mathieu
AU - Kuruvilla, Vinitha Mary
AU - Cavazos, Antonio
AU - Kaplan, Mecit
AU - Warmoes, Marc O.
AU - Veiga, Diogo Troggian
AU - Furudate, Ken
AU - Rojas-Sutterin, Shanti
AU - Haman, Andre
AU - Gareau, Yves
AU - Marinier, Anne
AU - Ma, Helen
AU - Harutyunyan, Karine
AU - Daher, May
AU - Garcia, Luciana Melo
AU - Al-Atrash, Gheath
AU - Piya, Sujan
AU - Ruvolo, Vivian
AU - Yang, Wentao
AU - Shanmugavelandy, Sriram Saravanan
AU - Feng, Ningping
AU - Gay, Jason
AU - Du, Di
AU - Yang, Jun J.
AU - Hoff, Fieke W.
AU - Kaminski, Marcin
AU - Tomczak, Katarzyna
AU - Eric Davis, R.
AU - Herranz, Daniel
AU - Ferrando, Adolfo
AU - Jabbour, Elias J.
AU - Emilia Di Francesco, M.
AU - Teachey, David T.
AU - Horton, Terzah M.
AU - Kornblau, Steven
AU - Rezvani, Katayoun
AU - Sauvageau, Guy
AU - Gagea, Mihai
AU - Andreeff, Michael
AU - Takahashi, Koichi
AU - Marszalek, Joseph R.
AU - Lorenzi, Philip L.
AU - Yu, Jiyang
AU - Tiziani, Stefano
AU - Hoang, Trang
AU - Konopleva, Marina
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85130332700&partnerID=8YFLogxK
U2 - 10.1038/s41467-022-30396-3
DO - 10.1038/s41467-022-30396-3
M3 - Article
C2 - 35589701
AN - SCOPUS:85130332700
SN - 2041-1723
VL - 13
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 2801
ER -