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- Title
Metabolic reprogramming induces resistance to anti-NOTCH1 therapies in T cell acute lymphoblastic leukemia.
- Authors
Herranz, Daniel; Ambesi-Impiombato, Alberto; Sudderth, Jessica; Sánchez-Martín, Marta; Belver, Laura; Tosello, Valeria; Xu, Luyao; Wendorff, Agnieszka A; Castillo, Mireia; Haydu, J Erika; Márquez, Javier; Matés, José M; Kung, Andrew L; Rayport, Stephen; Cordon-Cardo, Carlos; DeBerardinis, Ralph J; Ferrando, Adolfo A
- Abstract
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.
- Subjects
LYMPHOBLASTIC leukemia treatment; NOTCH genes; CELL metabolism; T cells; GENETIC mutation; GLUTAMINE; AUTOPHAGY; SALVAGE therapy; CANCER
- Publication
Nature Medicine, 2015, Vol 21, Issue 10, p1182
- ISSN
1078-8956
- Publication type
Article
- DOI
10.1038/nm.3955