TY - JOUR
T1 - Metabolic reprogramming induces resistance to anti-NOTCH1 therapies in T cell acute lymphoblastic leukemia
AU - Herranz, Daniel
AU - Ambesi-Impiombato, Alberto
AU - Sudderth, Jessica
AU - Sánchez-Martín, Marta
AU - Belver, Laura
AU - Tosello, Valeria
AU - Xu, Luyao
AU - Wendorff, Agnieszka A.
AU - Castillo, Mireia
AU - Haydu, J. Erika
AU - Márquez, Javier
AU - Matés, José M.
AU - Kung, Andrew L.
AU - Rayport, Stephen
AU - Cordon-Cardo, Carlos
AU - Deberardinis, Ralph J.
AU - Ferrando, Adolfo A.
PY - 2015/10/1
Y1 - 2015/10/1
N2 - 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.
AB - 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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U2 - 10.1038/nm.3955
DO - 10.1038/nm.3955
M3 - Article
AN - SCOPUS:84944076036
VL - 21
SP - 1182
EP - 1189
JO - Nature Medicine
JF - Nature Medicine
SN - 1078-8956
IS - 10
ER -