TY - JOUR
T1 - A Hyperactive Signalosome in Acute Myeloid Leukemia Drives Addiction to a Tumor-Specific Hsp90 Species
AU - Zong, Hongliang
AU - Gozman, Alexander
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 D.
AU - Chiosis, Gabriela
AU - Guzman, Monica L L.
N1 - Publisher Copyright:
© 2015 The Authors
PY - 2015
Y1 - 2015
N2 - 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.
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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U2 - 10.1016/j.celrep.2015.10.073
DO - 10.1016/j.celrep.2015.10.073
M3 - Article
C2 - 26628369
AN - SCOPUS:84959533029
SN - 2211-1247
VL - 13
SP - 2159
EP - 2173
JO - Cell reports
JF - Cell reports
IS - 10
ER -
