title: Heat shock protein 90 regulates the expression of Wilms tumor 1 protein in myeloid leukemias.
abstract: The aberrant overexpression of Wilms tumor 1 (WT1) in myeloid leukemia plays an important role in blast cell survival and resistance to chemotherapy. High expression of WT1 is also associated with relapse and shortened disease-free survival in patients. However, the mechanisms by which WT1 expression is regulated in leukemia remain unclear. Here, we report that heat shock protein 90 (Hsp90), which plays a critical role in the folding and maturation of several oncogenic proteins, associates with WT1 protein and stabilizes its expression. Pharmacologic inhibition of Hsp90 resulted in ubiquitination and subsequent proteasome-dependant degradation of WT1. RNAi-mediated silencing of WT1 reduced the survival of leukemia cells and increased the sensitivity of these cells to chemotherapy and Hsp90 inhibition. Furthermore, Hsp90 inhibitors 17-AAG [17-(allylamino)-17-demethoxygeldanamycin] and STA-9090 significantly reduced the growth of myeloid leukemia xenografts in vivo and effectively down-regulated the expression of WT1 and its downstream target proteins, c-Myc and Bcl-2. Collectively, our studies identify WT1 as a novel Hsp90 client and support the crucial role for the WT1-Hsp90 interaction in maintaining leukemia cell survival. These findings have significant implications for developing effective therapies for myeloid leukemias and offer a strategy to inhibit the oncogenic functions of WT1 by clinically available Hsp90 inhibitors.
authors.affiliation: Cancer Therapy and Research Center at The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA. bansals@uthscsa.edu
authors.forename: Hima
authors.initials: H
authors.lastname: Bansal
authors.forename: Sanjay
authors.initials: S
authors.lastname: Bansal
authors.forename: Manjeet
authors.initials: M
authors.lastname: Rao
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Foley
authors.forename: Jim
authors.initials: J
authors.lastname: Sang
authors.forename: David A
authors.initials: DA
authors.lastname: Proia
authors.forename: Ronald K
authors.initials: RK
authors.lastname: Blackman
authors.forename: Weiwen
authors.initials: W
authors.lastname: Ying
authors.forename: James
authors.initials: J
authors.lastname: Barsoum
authors.forename: Maria R
authors.initials: MR
authors.lastname: Baer
authors.forename: Kevin
authors.initials: K
authors.lastname: Kelly
authors.forename: Ronan
authors.initials: R
authors.lastname: Swords
authors.forename: Gail E
authors.initials: GE
authors.lastname: Tomlinson
authors.forename: Minoo
authors.initials: M
authors.lastname: Battiwalla
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Giles
authors.forename: Kelvin P
authors.initials: KP
authors.lastname: Lee
authors.forename: Swaminathan
authors.initials: S
authors.lastname: Padmanabhan
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D016227:Benzoquinones / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D020868:Gene Silencing; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology / Q000627:therapeutic use; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D054730:Protein Interaction Domains and Motifs; D017434:Protein Structure, Tertiary; D014230:Triazoles / Q000627:therapeutic use; D025721:WT1 Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C533237:STA 9090; D014230:Triazoles; D025721:WT1 Proteins; C112765:tanespimycin; D005047:Etoposide; D046988:Proteasome Endopeptidase Complex