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

Natalia Baran, Alessia Lodi, Yogesh Dhungana, Shelley Herbrich, Meghan Collins, Shannon Sweeney, Renu Pandey, Anna Skwarska, Shraddha Patel, Mathieu Tremblay, Vinitha Mary Kuruvilla, Antonio Cavazos, Mecit Kaplan, Marc O. Warmoes, Diogo Troggian Veiga, Ken Furudate, Shanti Rojas-Sutterin, Andre Haman, Yves Gareau, Anne Marinier, Helen Ma, Karine Harutyunyan, May Daher, Luciana Melo Garcia, Gheath Al-Atrash, Sujan Piya, Vivian Ruvolo, Wentao Yang, Sriram Saravanan Shanmugavelandy, Ningping Feng, Jason Gay, Di Du, Jun J. Yang, Fieke W. Hoff, Marcin Kaminski, Katarzyna Tomczak, R. Eric Davis, Daniel Herranz, Adolfo Ferrando, Elias J. Jabbour, M. Emilia Di Francesco, David T. Teachey, Terzah M. Horton, Steven Kornblau, Katayoun Rezvani, Guy Sauvageau, Mihai Gagea, Michael Andreeff, Koichi Takahashi, Joseph R. Marszalek, Philip L. Lorenzi, Jiyang Yu, Stefano Tiziani, Trang Hoang and Marina Konopleva ()
Additional contact information
Natalia Baran: The University of Texas MD Anderson Cancer Center
Alessia Lodi: The University of Texas at Austin
Yogesh Dhungana: St. Jude Children’s Research Hospital
Shelley Herbrich: The University of Texas MD Anderson Cancer Center
Meghan Collins: The University of Texas at Austin
Shannon Sweeney: The University of Texas at Austin
Renu Pandey: The University of Texas at Austin
Anna Skwarska: The University of Texas MD Anderson Cancer Center
Shraddha Patel: The University of Texas MD Anderson Cancer Center
Mathieu Tremblay: The University of Montreal
Vinitha Mary Kuruvilla: The University of Texas MD Anderson Cancer Center
Antonio Cavazos: The University of Texas MD Anderson Cancer Center
Mecit Kaplan: The University of Texas MD Anderson Cancer Center
Marc O. Warmoes: The University of Texas MD Anderson Cancer Center
Diogo Troggian Veiga: The Jackson Laboratory for Genomic Medicine
Ken Furudate: The University of Texas MD Anderson Cancer Center
Shanti Rojas-Sutterin: The University of Montreal
Andre Haman: The University of Montreal
Yves Gareau: The University of Montreal
Anne Marinier: The University of Montreal
Helen Ma: The University of Texas MD Anderson Cancer Center
Karine Harutyunyan: The University of Texas MD Anderson Cancer Center
May Daher: The University of Texas MD Anderson Cancer Center
Luciana Melo Garcia: The University of Texas MD Anderson Cancer Center
Gheath Al-Atrash: The University of Texas MD Anderson Cancer Center
Sujan Piya: The University of Texas MD Anderson Cancer Center
Vivian Ruvolo: The University of Texas MD Anderson Cancer Center
Wentao Yang: St. Jude Children’s Research Hospital
Sriram Saravanan Shanmugavelandy: The University of Texas MD Anderson Cancer Center
Ningping Feng: University of Texas M. D. Anderson Cancer Center
Jason Gay: University of Texas M. D. Anderson Cancer Center
Di Du: The University of Texas MD Anderson Cancer Center
Jun J. Yang: St. Jude Children’s Research Hospital
Fieke W. Hoff: The University of Texas MD Anderson Cancer Center
Marcin Kaminski: St. Jude Children’s Research Hospital
Katarzyna Tomczak: The University of Texas MD Anderson Cancer Center
R. Eric Davis: The University of Texas MD Anderson Cancer Center
Daniel Herranz: Cancer Institute of New Jersey
Adolfo Ferrando: Columbia University Irving Medical Center
Elias J. Jabbour: The University of Texas MD Anderson Cancer Center
M. Emilia Di Francesco: The University of Texas MD Anderson Cancer Center
David T. Teachey: The University of Pennsylvania
Terzah M. Horton: Baylor College of Medicine
Steven Kornblau: The University of Texas MD Anderson Cancer Center
Katayoun Rezvani: The University of Texas MD Anderson Cancer Center
Guy Sauvageau: The University of Montreal
Mihai Gagea: The University of Texas MD Anderson Cancer Center
Michael Andreeff: The University of Texas MD Anderson Cancer Center
Koichi Takahashi: The University of Texas MD Anderson Cancer Center
Joseph R. Marszalek: University of Texas M. D. Anderson Cancer Center
Philip L. Lorenzi: The University of Texas MD Anderson Cancer Center
Jiyang Yu: St. Jude Children’s Research Hospital
Stefano Tiziani: The University of Texas at Austin
Trang Hoang: The University of Montreal
Marina Konopleva: The University of Texas MD Anderson Cancer Center

Nature Communications, 2022, vol. 13, issue 1, 1-20

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-30396-3

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