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Cited by 208

The DOI matches its Crossref record; 11 of the 11 references it cites were found in a registry or an index.

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

Open access
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·2015·Nature Medicine

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.

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Crossref · 10.1038/nm.3955

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Metadata

Authors
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.
Venue
Nature Medicine
Published
2015-09-21
Volume
21
Issue
10
Pages
1182-1189
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
OpenAlex
W2196885702
Cited by
208
References
11
FWCI
21.67
Type
journal article
Language
en
Open access
green

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