Journal
NATURE MEDICINE
Volume 21, Issue 10, Pages 1182-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.3955
Keywords
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Funding
- US National Institutes of Health [R01CA129382, CA120196]
- Stand Up To Cancer Innovative Research Award
- Swim Across America Foundation
- Junta de Andalucia, Spain [CVI-6656]
- Leukemia and Lymphoma Society
- Rally Foundation
- Lymphoma Research Foundation
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Activating mutations in NOTCH1 are common in T cell acute lymphoblastic leukemia (T-ALL). Here we identify glutaminolysis as a critical pathway for leukemia cell growth downstream of NOTCH1 and a key determinant of the response to anti-NOTCH1 therapies in vivo. Mechanistically, inhibition of NOTCH1 signaling in T-ALL induces a metabolic shutdown, with prominent inhibition of glutaminolysis and triggers autophagy as a salvage pathway supporting leukemia cell metabolism. Consequently, inhibition of glutaminolysis and inhibition of autophagy strongly and synergistically enhance the antileukemic effects of anti-NOTCH1 therapy in mice harboring T-ALL. Moreover, we demonstrate that Pten loss upregulates glycolysis and consequently rescues leukemic cell metabolism, thereby abrogating the antileukemic effects of NOTCH1 inhibition. Overall, these results identify glutaminolysis as a major node in cancer metabolism controlled by NOTCH1 and as therapeutic target for the treatment of T-ALL.
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