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

Authors :
Andrew L. Kung
J. Erika Haydu
Jessica Sudderth
Alberto Ambesi-Impiombato
Agnieszka A. Wendorff
José M. Matés
Javier Márquez
Marta Sanchez-Martin
Adolfo A. Ferrando
Carlos Cordon-Cardo
Luyao Xu
Valeria Tosello
Ralph J. DeBerardinis
Mireia Castillo
Stephen Rayport
Laura Belver
Daniel Herranz
Source :
Nature medicine
Publication Year :
2015
Publisher :
Springer Science and Business Media LLC, 2015.

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.

Details

ISSN :
1546170X and 10788956
Volume :
21
Database :
OpenAIRE
Journal :
Nature Medicine
Accession number :
edsair.doi.dedup.....94a334bc65a7eee28a4d3707e5c428d6
Full Text :
https://doi.org/10.1038/nm.3955