title: Heat shock protein 90 inhibition results in altered downstream signaling of mutant KIT and exerts synergistic effects on Kasumi-1 cells when combining with histone deacetylase inhibitor.
abstract: KIT mutations may be associated with a poor prognosis in t(8;21) AML. Heat shock protein 90 (Hsp90) is a molecular chaperone frequently used by cancer cells to stabilize mutant oncoproteins. Inhibition of Hsp90 by 17-allylamino-17-demethoxygeldanamycin (17-AAG) disrupted downstream signaling pathways of mutant KIT in Kasumi-1 cells. AML1-ETO fusion gene and mutated KIT act as "two-hit" factors in Kasumi-1 cells. Histone deacetylation (HDAC) inhibitors sodium phenylbutyrate (PB) and valproic acid (VPA) block AML1-ETO. Co-treatment with 17-AAG and PB or 17-AAG and VPA resulted in a synergistic effect in Kasumi-1 cells. Our results confirmed that Hsp90 and mutated KIT were valid molecular targets in the therapy of AML.
authors.affiliation: Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, PR China. drwjyu@163.com
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Yu
authors.forename: Jianxiang
authors.initials: J
authors.lastname: Wang
authors.forename: Jie
authors.initials: J
authors.lastname: Jin
authors.forename: Wenbin
authors.initials: W
authors.lastname: Qian
authors.forename: Jiejing
authors.initials: J
authors.lastname: Qian
authors.forename: Yizhi
authors.initials: Y
authors.lastname: Cheng
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology*; D016227:Benzoquinones / Q000008:administration & dosage* / Q000494:pharmacology; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D006801:Humans; D047029:Lactams, Macrocyclic / Q000008:administration & dosage* / Q000494:pharmacology; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D050505:Mutant Proteins / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D056572:Histone Deacetylase Inhibitors; D047029:Lactams, Macrocyclic; D050505:Mutant Proteins; D047428:Protein Kinase Inhibitors; C112765:tanespimycin; D019009:Proto-Oncogene Proteins c-kit