title: A Hyperactive Signalosome in Acute Myeloid Leukemia Drives Addiction to a Tumor-Specific Hsp90 Species.
abstract: Acute myeloid leukemia (AML) is a heterogeneous and fatal disease with an urgent need for improved therapeutic regimens given that most patients die from relapsed disease. Irrespective of mutation status, the development of aggressive leukemias is enabled by increasing dependence on signaling networks. We demonstrate that a hyperactive signalosome drives addiction of AML cells to a tumor-specific Hsp90 species (teHsp90). Through genetic, environmental, and pharmacologic perturbations, we demonstrate a direct and quantitative link between hyperactivated signaling pathways and apoptotic sensitivity of AML to teHsp90 inhibition. Specifically, we find that hyperactive JAK-STAT and PI3K-AKT signaling networks are maintained by teHsp90 and, in fact, gradual activation of these networks drives tumors increasingly dependent on teHsp90. Thus, although clinically aggressive AML survives via signalosome activation, this addiction creates a vulnerability that can be exploited with Hsp90-directed therapy.
authors.affiliation: Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Hongliang
authors.initials: H
authors.lastname: Zong
authors.affiliation: Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, New York, NY 10065, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Gozman
authors.affiliation: Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, New York, NY 10065, USA.
authors.forename: Eloisi
authors.initials: E
authors.lastname: Caldas-Lopes
authors.affiliation: Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, New York, NY 10065, USA.
authors.forename: Tony
authors.initials: T
authors.lastname: Taldone
authors.affiliation: Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Sturgill
authors.affiliation: Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Brennan
authors.affiliation: Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, New York, NY 10065, USA.
authors.forename: Stefan O
authors.initials: SO
authors.lastname: Ochiana
authors.affiliation: Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, New York, NY 10065, USA.
authors.forename: Erica M
authors.initials: EM
authors.lastname: Gomes-DaGama
authors.affiliation: Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Siddhartha
authors.initials: S
authors.lastname: Sen
authors.affiliation: Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, New York, NY 10065, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Rodina
authors.affiliation: Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, New York, NY 10065, USA.
authors.forename: John
authors.initials: J
authors.lastname: Koren
authors.affiliation: James P. Wilmot Cancer Center, University of Rochester, Rochester, NY 14642, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Becker
authors.affiliation: Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, New York, NY 10065, USA.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rudin
authors.affiliation: Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Ari
authors.initials: A
authors.lastname: Melnick
authors.affiliation: HOPP, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
authors.forename: Ross L
authors.initials: RL
authors.lastname: Levine
authors.affiliation: Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Gail J
authors.initials: GJ
authors.lastname: Roboz
authors.affiliation: Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Nimer
authors.affiliation: Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, New York, NY 10065, USA. Electronic address: chiosisg@mskcc.org.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Chiosis
authors.affiliation: Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA. Electronic address: mlg2007@med.cornell.edu.
authors.forename: Monica L
authors.initials: ML
authors.lastname: Guzman
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D052117:Benzodioxoles / Q000494:pharmacology; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D011687:Purines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D052117:Benzodioxoles; D018841:HSP90 Heat-Shock Proteins; D011687:Purines; C526550:9H-purine-9-propanamine, 6-amino-8-((6-iodo-1,3-benzodioxol-5-yl)thio)-N-(1-methylethyl)-