A Hyperactive Signalosome in Acute Myeloid Leukemia Drives Addiction to a Tumor-Specific Hsp90 Species

Hongliang Zong; Alexander Gozman; Eloisi Caldas-Lopes; Tony Taldone; Eric Sturgill; Sarah Brennan; Stefan O Ochiana; Erica M Gomes-DaGama; Siddhartha Sen; Anna Rodina; John Koren, 3rd; Michael W Becker; Charles M Rudin; Ari Melnick; Ross L Levine; Gail J Roboz; Stephen D Nimer; Gabriela Chiosis; Monica L Guzman

doi:10.1016/j.celrep.2015.10.073

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A Hyperactive Signalosome in Acute Myeloid Leukemia Drives Addiction to a Tumor-Specific Hsp90 Species

Journal article

Open access

Peer reviewed

A Hyperactive Signalosome in Acute Myeloid Leukemia Drives Addiction to a Tumor-Specific Hsp90 Species

Hongliang Zong, Alexander Gozman, Eloisi Caldas-Lopes, Tony Taldone, Eric Sturgill, Sarah Brennan, Stefan O Ochiana, Erica M Gomes-DaGama, Siddhartha Sen, Anna Rodina, …

Cell reports (Cambridge), Vol.13(10), pp.2159-2173

2015-12-15

DOI: https://doi.org/10.1016/j.celrep.2015.10.073

PMCID: PMC4699804

PMID: 26628369

Abstract

Apoptosis - drug effects

Leukemia, Myeloid, Acute - pathology

Purines - pharmacology

Humans

Leukemia, Myeloid, Acute - metabolism

Xenograft Model Antitumor Assays

Animals

Signal Transduction - drug effects

HSP90 Heat-Shock Proteins - antagonists & inhibitors

Mice, Nude

HSP90 Heat-Shock Proteins - metabolism

Signal Transduction - physiology

Antineoplastic Agents - pharmacology

Mice

Apoptosis - physiology

Benzodioxoles - pharmacology

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.

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Collaboration types: Domestic collaboration
Citation topics: 1 Clinical & Life Sciences; 1.25 Molecular & Cell Biology - Cancer, Autophagy & Apoptosis; 1.25.512 Hsp70
Web Of Science research areas: Cell Biology
ESI research areas: Molecular Biology & Genetics

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Title: A Hyperactive Signalosome in Acute Myeloid Leukemia Drives Addiction to a Tumor-Specific Hsp90 Species
Creators: Hongliang Zong - Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA
Alexander Gozman - Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, New York, NY 10065, USA
Eloisi Caldas-Lopes - Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, New York, NY 10065, USA
Tony Taldone - Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, New York, NY 10065, USA
Eric Sturgill - Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA
Sarah Brennan - Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA
Stefan O Ochiana - Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, New York, NY 10065, USA
Erica M Gomes-DaGama - Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, New York, NY 10065, USA
Siddhartha Sen - Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA
Anna Rodina - Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, New York, NY 10065, USA
John Koren, 3rd - Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, New York, NY 10065, USA
Michael W Becker - James P. Wilmot Cancer Center, University of Rochester, Rochester, NY 14642, USA
Charles M Rudin - Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, New York, NY 10065, USA
Ari Melnick - Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA
Ross L Levine - HOPP, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA
Gail J Roboz - Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA
Stephen D Nimer - Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA
Gabriela Chiosis - Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, New York, NY 10065, USA. Electronic address: chiosisg@mskcc.org
Monica L Guzman - Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA. Electronic address: mlg2007@med.cornell.edu
Publication Details: Cell reports (Cambridge), Vol.13(10), pp.2159-2173
Publisher: United States
Grant note: UL1 RR024996 / NCRR NIH HHS R01 CA155226 / NCI NIH HHS DP2 OD007399 / NIH HHS 1 DP2 OD007399-01 / NIH HHS UL1RR024996 / NCRR NIH HHS R01 CA166835 / NCI NIH HHS R01 CA102031 / NCI NIH HHS UL1 TR000457 / NCATS NIH HHS P30 CA008748 / NCI NIH HHS R01 CA172546 / NCI NIH HHS P50 CA192937 / NCI NIH HHS R01 CA-166835 / NCI NIH HHS P01 CA186866 / NCI NIH HHS F32 CA192786 / NCI NIH HHS UL1TR00457 / NCATS NIH HHS
Academic Unit: Leadership Department; Miller School of Medicine; Sylvester Comprehensive Cancer Center
Language: English
Resource Type: Journal article
PMID: 26628369
PMCID: PMC4699804
Record Identifier: 991031575430002976