title: Autophagy mediates proteolysis of NPM1 and HEXIM1 and sensitivity to BET inhibition in AML cells.
abstract: The mechanisms underlying activation of the BET pathway in AML cells remain poorly understood. We have discovered that autophagy is activated in acute leukemia cells expressing mutant nucleophosmin 1 (NPMc+) or MLL-fusion proteins. Autophagy activation results in the degradation of NPM1 and HEXIM1, two negative regulators of BET pathway activation. Inhibition of autophagy with pharmacologic inhibitors or through knocking down autophagy-related gene 5 (Atg5) expression increases the expression of both NPM1 and HEXIM1. The Brd4 inhibitors JQ1 and I-BET-151 also inhibit autophagy and increase NPM1 and HEXIM1 expression. We conclude that the degradation of NPM1 and HEXIM1 through autophagy in certain AML subsets contributes to the activation of the BET pathway in these cells.
authors.affiliation: Stanford Cancer Institute, Stanford University, Stanford, California, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Huang
authors.affiliation: Division of Hematology, Department of Medicine, Stanford University, Stanford, California, USA.
authors.forename: Jacqueline S
authors.initials: JS
authors.lastname: Garcia
authors.affiliation: Division of Hematology, Department of Medicine, Stanford University, Stanford, California, USA.|Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Thomas
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Stanford Cancer Institute, Stanford University, Stanford, California, USA.
authors.forename: Le Xuan Truong
authors.initials: LX
authors.lastname: Nguyen
authors.affiliation: Division of Hematology, Department of Medicine, Stanford University, Stanford, California, USA.|Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Chan
authors.affiliation: Stanford Cancer Institute, Stanford University, Stanford, California, USA.|Division of Hematology, Department of Medicine, Stanford University, Stanford, California, USA.|Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California, USA.
authors.forename: Ravindra
authors.initials: R
authors.lastname: Majeti
authors.affiliation: Stanford Cancer Institute, Stanford University, Stanford, California, USA.|Division of Hematology, Department of Medicine, Stanford University, Stanford, California, USA.
authors.forename: Bruno C
authors.initials: BC
authors.lastname: Medeiros
authors.affiliation: Stanford Cancer Institute, Stanford University, Stanford, California, USA.|Division of Hematology, Department of Medicine, Stanford University, Stanford, California, USA.
authors.forename: Beverly S
authors.initials: BS
authors.lastname: Mitchell
mesh_terms: D001343:Autophagy / Q000235:genetics; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism*; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000090243:Nucleophosmin; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D011506:Proteins / Q000037:antagonists & inhibitors*; D059748:Proteolysis; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000037:antagonists & inhibitors; D000092468:Bromodomain Containing Proteins
chemical_list: D018797:Cell Cycle Proteins; D051788:Myeloid-Lymphoid Leukemia Protein; D009687:Nuclear Proteins; D000090243:Nucleophosmin; D015514:Oncogene Proteins, Fusion; D011506:Proteins; D016601:RNA-Binding Proteins; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C476123:HEXIM1 protein, human; C000716967:NPM1 protein, human; C000624329:bromodomain and extra-terminal domain protein, human
keywords: AML; BET inhibitors; HEXIM1; NPM1; autophagy