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 O. Ochiana, Erica M M. Gomes-DaGama, Siddhartha Sen, Anna Rodina, John Koren, Michael W W. Becker, Charles M M. Rudin, Ari Melnick, Ross L L. Levine, Gail J J. Roboz, Stephen D Nimer, Gabriela Chiosis, Monica L L. Guzman

Research output: Contribution to journalArticle

24 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2159-2173
Number of pages15
JournalCell Reports
Volume13
Issue number10
DOIs
StatePublished - 2015

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Acute Myeloid Leukemia
Tumors
Chemical activation
Neoplasms
Phosphatidylinositol 3-Kinases
Myeloid Cells
Leukemia
Mutation
Therapeutics

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Zong, H., Gozman, A., Caldas-Lopes, E., Taldone, T., Sturgill, E., Brennan, S., ... Guzman, ML. L. (2015). A Hyperactive Signalosome in Acute Myeloid Leukemia Drives Addiction to a Tumor-Specific Hsp90 Species. Cell Reports, 13(10), 2159-2173. https://doi.org/10.1016/j.celrep.2015.10.073

A Hyperactive Signalosome in Acute Myeloid Leukemia Drives Addiction to a Tumor-Specific Hsp90 Species. / Zong, Hongliang; Gozman, Alexander; Caldas-Lopes, Eloisi; Taldone, Tony; Sturgill, Eric; Brennan, Sarah; Ochiana, Stefan O O.; Gomes-DaGama, Erica M M.; Sen, Siddhartha; Rodina, Anna; Koren, John; Becker, Michael W W.; Rudin, Charles M M.; Melnick, Ari; Levine, Ross L L.; Roboz, Gail J J.; Nimer, Stephen D; Chiosis, Gabriela; Guzman, Monica L L.

In: Cell Reports, Vol. 13, No. 10, 2015, p. 2159-2173.

Research output: Contribution to journalArticle

Zong, H, Gozman, A, Caldas-Lopes, E, Taldone, T, Sturgill, E, Brennan, S, Ochiana, SOO, Gomes-DaGama, EMM, Sen, S, Rodina, A, Koren, J, Becker, MWW, Rudin, CMM, Melnick, A, Levine, RLL, Roboz, GJJ, Nimer, SD, Chiosis, G & Guzman, MLL 2015, 'A Hyperactive Signalosome in Acute Myeloid Leukemia Drives Addiction to a Tumor-Specific Hsp90 Species', Cell Reports, vol. 13, no. 10, pp. 2159-2173. https://doi.org/10.1016/j.celrep.2015.10.073
Zong, Hongliang ; Gozman, Alexander ; Caldas-Lopes, Eloisi ; Taldone, Tony ; Sturgill, Eric ; Brennan, Sarah ; Ochiana, Stefan O O. ; Gomes-DaGama, Erica M M. ; Sen, Siddhartha ; Rodina, Anna ; Koren, John ; Becker, Michael W W. ; Rudin, Charles M M. ; Melnick, Ari ; Levine, Ross L L. ; Roboz, Gail J J. ; Nimer, Stephen D ; Chiosis, Gabriela ; Guzman, Monica L L. / A Hyperactive Signalosome in Acute Myeloid Leukemia Drives Addiction to a Tumor-Specific Hsp90 Species. In: Cell Reports. 2015 ; Vol. 13, No. 10. pp. 2159-2173.
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AU - Caldas-Lopes, Eloisi

AU - Taldone, Tony

AU - Sturgill, Eric

AU - Brennan, Sarah

AU - Ochiana, Stefan O O.

AU - Gomes-DaGama, Erica M M.

AU - Sen, Siddhartha

AU - Rodina, Anna

AU - Koren, John

AU - Becker, Michael W W.

AU - Rudin, Charles M M.

AU - Melnick, Ari

AU - Levine, Ross L L.

AU - Roboz, Gail J J.

AU - Nimer, Stephen D

AU - Chiosis, Gabriela

AU - Guzman, Monica L L.

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AB - 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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