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.
N1 - Funding Information:
We are grateful to J. Aster (Brigham and Women’s Hospital, Harvard Medical School) for the MigR1-NOTCH1 L1601P ∆PEST vector, D. Vignali (University of Pittsburgh) for the pMSCV-mCherry FP vector, W. Pear (Abramson Family Cancer Research Institute, University of Pennsylvania) for the MigR1 vector, B. Ebert (Dana-Farber Cancer Research Institute) for the pL-CRISPR.EFS.GFP vector, P. Pandolfi (Beth Israel Deaconess Medical Center, Harvard Medical School) for the Pten conditional knockout mouse, T. Ludwig (Columbia University Medical Center) for the Rosa26Cre-ERT2/+ mouse, M. Komatsu (Tokyo Metropolitan Institute of Medical Science) for the Atg7 conditional knockout mouse, S. Indraccolo (Istituto di Ricovero e Cura a Carattere Scientifico) for xenograft T-ALL cells and R. Baer and C. Lopez-Otin for helpful discussions and revision of the manuscript. This work was supported by the US National Institutes of Health grants R01CA129382 and CA120196, the Stand Up To Cancer Innovative Research Award and the Swim Across America Foundation (A.A.F.). J.M. and J.M.M. were supported by CVI-6656 (Junta de Andalucía, Spain). D.H. is supported by the Leukemia and Lymphoma Society. M.S.-M. and A.A.W. are supported by the Rally Foundation. L.B. is supported by the Lymphoma Research Foundation.
Publisher Copyright:
© 2015 Nature America, Inc. All rights reserved.
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.
UR - http://www.scopus.com/inward/record.url?scp=84944076036&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84944076036&partnerID=8YFLogxK
U2 - 10.1038/nm.3955
DO - 10.1038/nm.3955
M3 - Article
C2 - 26390244
AN - SCOPUS:84944076036
SN - 1078-8956
VL - 21
SP - 1182
EP - 1189
JO - Nature Medicine
JF - Nature Medicine
IS - 10
ER -