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Nat Med. 2015 Oct;21(10):1182-9. doi: 10.1038/nm.3955. Epub 2015 Sep 21.

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

Author information

1
Institute for Cancer Genetics, Columbia University, New York, New York, USA.
2
Children's Medical Center Research Institute, University of Texas-Southwestern Medical Center, Dallas, Texas, USA.
3
Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
4
Department of Molecular Biology and Biochemistry, Faculty of Sciences, Campus de Teatinos, University of Málaga-Instituto de Investigación Biomédica de Málaga, Málaga, Spain.
5
Department of Pediatrics, Columbia University Medical Center, New York, New York, USA.
6
Department of Psychiatry, Columbia University Medical Center, New York, New York, USA.
7
Department of Pathology, Columbia University Medical Center, New York, New York, USA.

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.

PMID:
26390244
PMCID:
PMC4598309
DOI:
10.1038/nm.3955
[Indexed for MEDLINE]
Free PMC Article

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