NDLI: Heat shock protein 90 regulates the expression of Wilms tumor 1 protein in myeloid leukemias

Content Provider	PubMed Central
Author	Bansal, Hima Bansal, Sanjay Rao, Manjeet Foley, Kevin P. Sang, Jim Proia, David A. Blackman, Ronald K. Ying, Weiwen Barsoum, James Baer, Maria R. Kelly, Kevin Swords, Ronan Tomlinson, Gail E. Battiwalla, Minoo Giles, Francis J. Lee, Kelvin P. Padmanabhan, Swaminathan
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 func-tions of WT1 by clinically available Hsp90 inhibitors.
Related Links	http://dx.doi.org/10.1182/blood-2009-10-247239
Ending Page	4599
Page Count	9
Starting Page	4591
File Format	PDF
ISSN	00064971
e-ISSN	15280020
Journal	Blood
Issue Number	22
Volume Number	116
Language	English
Publisher	American Society of Hematology
Publisher Date	2010-11-25
Access Restriction	Open
Rights Holder	American Society of Hematology
Subject Keyword	Immunology Cell Biology Biochemistry Hematology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cell Biology Hematology Biochemistry Immunology

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