title: Direct reversal of glucocorticoid resistance by AKT inhibition in acute lymphoblastic leukemia.
abstract: Glucocorticoid resistance is a major driver of therapeutic failure in T cell acute lymphoblastic leukemia (T-ALL). Here, we identify the AKT1 kinase as a major negative regulator of the NR3C1 glucocorticoid receptor protein activity driving glucocorticoid resistance in T-ALL. Mechanistically, AKT1 impairs glucocorticoid-induced gene expression by direct phosphorylation of NR3C1 at position S134 and blocking glucocorticoid-induced NR3C1 translocation to the nucleus. Moreover, we demonstrate that loss of PTEN and consequent AKT1 activation can effectively block glucocorticoid-induced apoptosis and induce resistance to glucocorticoid therapy. Conversely, pharmacologic inhibition of AKT with MK2206 effectively restores glucocorticoid-induced NR3C1 translocation to the nucleus, increases the response of T-ALL cells to glucocorticoid therapy, and effectively reverses glucocorticoid resistance in vitro and in vivo.
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, NY, 10032, USA.|UOC Immunologia e Diagnostica Molecolare Oncologica, Istituto Oncologico Veneto-IRCCS, Padova, 35128, Italy.|Dipartimento di Scienze Chirurgiche, Oncologiche e Gastroenterologiche, Universita' di Padova, Padova, Padova, Veneto, 35128, Italy.
authors.forename: Erich
authors.initials: E
authors.lastname: Piovan
authors.affiliation: Department of Biomedical Informatics, Columbia University, New York, NY, 10032, USA.|Department of Systems Biology, Columbia University, New York, NY, 10032, USA.
authors.forename: Jiyang
authors.initials: J
authors.lastname: Yu
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, NY, 10032, USA.|Istituto Oncologico Veneto, IRCCS, Padova, Veneto, 35128, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Tosello
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, NY, 10032, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Herranz
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, NY, 10032, USA.
authors.forename: Alberto
authors.initials: A
authors.lastname: Ambesi-Impiombato
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, NY, 10032, USA.
authors.forename: Ana Carolina
authors.initials: AC
authors.lastname: Da Silva
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, NY, 10032, USA.
authors.forename: Marta
authors.initials: M
authors.lastname: Sanchez-Martin
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, NY, 10032, USA.
authors.forename: Arianne
authors.initials: A
authors.lastname: Perez-Garcia
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, NY, 10032, USA.
authors.forename: Isaura
authors.initials: I
authors.lastname: Rigo
authors.affiliation: Department of Pathology, Mount Sinai School of Medicine, New York, NY, 10029, USA.
authors.forename: Mireia
authors.initials: M
authors.lastname: Castillo
authors.affiliation: UOC Immunologia e Diagnostica Molecolare Oncologica, Istituto Oncologico Veneto-IRCCS, Padova, 35128, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Indraccolo
authors.affiliation: Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065 USA.
authors.forename: Justin R
authors.initials: JR
authors.lastname: Cross
authors.affiliation: Antitumor Assessment Core Facility, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065 USA.
authors.forename: Elisa
authors.initials: E
authors.lastname: de Stanchina
authors.affiliation: Department of Medicine, Albert Einstein School of Medicine, Bronx, NY, 10461, USA.|New York Medical College and Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Paietta
authors.affiliation: Department of Medicine, Albert Einstein School of Medicine, Bronx, NY, 10461, USA.|New York Medical College and Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
authors.forename: Janis
authors.initials: J
authors.lastname: Racevskis
authors.affiliation: Hematology Department, Shaare Zedek Hospital, Jerusalem, 91031, Israel.
authors.forename: Jacob M
authors.initials: JM
authors.lastname: Rowe
authors.affiliation: Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Martin S
authors.initials: MS
authors.lastname: Tallman
authors.affiliation: Dipartimento di Salute della Donna e del Bambino, Università di Padova, via Giustiniani 3, 35128, Padova, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Basso
authors.affiliation: Department of Pediatric Oncology/Hematology, Erasmus MC-Sophia Children's Hospital, Rotterdam, South Holland, 010 7040704, the Netherlands.
authors.forename: Jules P
authors.initials: JP
authors.lastname: Meijerink
authors.affiliation: Department of Pathology, Mount Sinai School of Medicine, New York, NY, 10029, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Cordon-Cardo
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, NY, 10032, USA.|Department of Biomedical Informatics, Columbia University, New York, NY, 10032, USA.|Department of Systems Biology, Columbia University, New York, NY, 10032, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Califano
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, NY, 10032, USA.|Department of Pathology, Mount Sinai School of Medicine, New York, NY, 10029, USA.|Department of Pediatrics, Columbia University Medical Center, New York, NY, 10032, USA.
authors.forename: Adolfo A
authors.initials: AA
authors.lastname: Ferrando
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D003907:Dexamethasone / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D051059:PTEN Phosphohydrolase / Q000502:physiology; D010766:Phosphorylation; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000502:physiology; D011965:Receptors, Glucocorticoid / Q000378:metabolism
chemical_list: D006575:Heterocyclic Compounds, 3-Ring; C548887:MK 2206; C497713:NR3C1 protein, human; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase