Metabolic reprogramming induces resistance to anti-NOTCH1 therapies in T cell acute lymphoblastic leukemia

Daniel Herranz, Alberto Ambesi-Impiombato, Jessica Sudderth, Marta Sánchez-Martín, Laura Belver, Valeria Tosello, Luyao Xu, Agnieszka A. Wendorff, Mireia Castillo, J. Erika Haydu, Javier Márquez, José M. Matés, Andrew L. Kung, Stephen Rayport, Carlos Cordon-Cardo, Ralph J. Deberardinis, Adolfo A. Ferrando

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96 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1182-1189
Number of pages8
JournalNature medicine
Volume21
Issue number10
DOIs
StatePublished - Oct 1 2015

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Herranz, D., Ambesi-Impiombato, A., Sudderth, J., Sánchez-Martín, M., Belver, L., Tosello, V., Xu, L., Wendorff, A. A., Castillo, M., Haydu, J. E., Márquez, J., Matés, J. M., Kung, A. L., Rayport, S., Cordon-Cardo, C., Deberardinis, R. J., & Ferrando, A. A. (2015). Metabolic reprogramming induces resistance to anti-NOTCH1 therapies in T cell acute lymphoblastic leukemia. Nature medicine, 21(10), 1182-1189. https://doi.org/10.1038/nm.3955