Journal
NATURE COMMUNICATIONS
Volume 13, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-022-30396-3
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Funding
- Cancer Prevention and Research Institute of Texas (CPRIT)
- National Institutes of Health (NIH) [R01CA231364]
- Leukemia SPORE [P50 CA100632, CPRIT RP180309, R01GM134382, P30CA016672]
- NIH/National Cancer Institute
- CPRIT grant [RP130397]
- NIH [S10OD012304-01]
- Canadian Cancer Society [704867]
- Oncopole-Cancer Research Society-Fonds de recherche du Quebec [265879]
- Canadian Institute for Health Research [PJT-148943]
- Genome Canada
- Genome Quebec
- Cole Foundation
- Agilent
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The study reveals that T-ALL is commonly driven by activating mutations in NOTCH1, which directly relates to elevated OxPhos gene expression. Inhibition of OxPhos disrupts leukemia cell growth and induces metabolic reprogramming into glutaminolysis. Combining OxPhos blockade with inducible knock-down of glutaminase shows synthetic lethality in NOTCH1-mutated T-ALL mice.
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. Notch1 is frequently activated promoting T-cell acute lymphoblastic leukaemia (T-ALL). Here, the authors show that Notch1 induces oxidative phosphorylation dependency in T-ALL and synergism when inhibiting both mitochondrial complex I and glutaminolysis in preclinical murine and human xenograft models.
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