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

doi:10.1038/nm.3955

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

Istituto Oncologico Veneto

Research output: Contribution to journal › Article › peer-review

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 language	English
Pages (from-to)	1182-1189
Number of pages	8
Journal	Nature Medicine
Volume	21
Issue number	10
DOIs	https://doi.org/10.1038/nm.3955
Publication status	Published - Oct 1 2015

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)
Medicine(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

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

In: Nature Medicine, Vol. 21, No. 10, 01.10.2015, p. 1182-1189.

Research output: Contribution to journal › Article › peer-review

Herranz, D, Ambesi-Impiombato, A, Sudderth, J, Sánchez-Martín, M, Belver, L, Tosello, V, Xu, L, Wendorff, AA, Castillo, M, Haydu, JE, Márquez, J, Matés, JM, Kung, AL, Rayport, S, Cordon-Cardo, C, Deberardinis, RJ & Ferrando, AA 2015, 'Metabolic reprogramming induces resistance to anti-NOTCH1 therapies in T cell acute lymphoblastic leukemia', Nature Medicine, vol. 21, no. 10, pp. 1182-1189. https://doi.org/10.1038/nm.3955

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. / Metabolic reprogramming induces resistance to anti-NOTCH1 therapies in T cell acute lymphoblastic leukemia. In: Nature Medicine. 2015 ; Vol. 21, No. 10. pp. 1182-1189.

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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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AU - Márquez, Javier

AU - Matés, José M.

AU - Kung, Andrew L.

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