title: Metabolic reprogramming induces resistance to anti-NOTCH1 therapies in T cell acute lymphoblastic leukemia.
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.
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, New York, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Herranz
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, New York, USA.
authors.forename: Alberto
authors.initials: A
authors.lastname: Ambesi-Impiombato
authors.affiliation: Children's Medical Center Research Institute, University of Texas-Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Sudderth
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, New York, USA.
authors.forename: Marta
authors.initials: M
authors.lastname: Sánchez-Martín
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, New York, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Belver
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, New York, USA.
authors.forename: Valeria
authors.initials: V
authors.lastname: Tosello
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, New York, USA.
authors.forename: Luyao
authors.initials: L
authors.lastname: Xu
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, New York, USA.
authors.forename: Agnieszka A
authors.initials: AA
authors.lastname: Wendorff
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Mireia
authors.initials: M
authors.lastname: Castillo
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, New York, USA.
authors.forename: J Erika
authors.initials: JE
authors.lastname: Haydu
authors.affiliation: Department of Molecular Biology and Biochemistry, Faculty of Sciences, Campus de Teatinos, University of Málaga-Instituto de Investigación Biomédica de Málaga, Málaga, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Márquez
authors.affiliation: Department of Molecular Biology and Biochemistry, Faculty of Sciences, Campus de Teatinos, University of Málaga-Instituto de Investigación Biomédica de Málaga, Málaga, Spain.
authors.forename: José M
authors.identifier: http://orcid.org/0000-0001-9795-1993
authors.initials: JM
authors.lastname: Matés
authors.affiliation: Department of Pediatrics, Columbia University Medical Center, New York, New York, USA.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Kung
authors.affiliation: Department of Psychiatry, Columbia University Medical Center, New York, New York, USA.
authors.forename: Stephen
authors.identifier: http://orcid.org/0000-0001-9755-7486
authors.initials: S
authors.lastname: Rayport
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Carlos
authors.identifier: http://orcid.org/0000-0003-0858-5624
authors.initials: C
authors.lastname: Cordon-Cardo
authors.affiliation: Children's Medical Center Research Institute, University of Texas-Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Ralph J
authors.initials: RJ
authors.lastname: DeBerardinis
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, New York, USA.|Department of Pediatrics, Columbia University Medical Center, New York, New York, USA.|Department of Pathology, Columbia University Medical Center, New York, New York, USA.
authors.forename: Adolfo A
authors.initials: AA
authors.lastname: Ferrando
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D005973:Glutamine / Q000378:metabolism; D051379:Mice; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D005973:Glutamine