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: Hima Bansal, Sanjay Bansal, Manjeet Rao, Kevin P Foley, Jim Sang, David A Proia, Ronald K Blackman, Weiwen Ying, James Barsoum, Maria R Baer, Kevin Kelly, Ronan Swords, Gail E Tomlinson, Minoo Battiwalla, Francis J Giles, Kelvin P Lee, Swaminathan Padmanabhan
• Journal: Blood (Blood) Vol. 116 Issue 22 Pg. 4591-9 (Nov 25 2010) ISSN: 1528-0020 [Electronic] United States
• PMID: 20651072 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Phytogenic
• Benzoquinones
• HSP90 Heat-Shock Proteins
• Lactams, Macrocyclic
• STA 9090
• Triazoles
• WT1 Proteins
• tanespimycin
• Etoposide
• Proteasome Endopeptidase Complex

Topics

• Animals
• Antineoplastic Agents, Phytogenic (pharmacology)
• Apoptosis (drug effects)
• Benzoquinones (pharmacology, therapeutic use)
• Cell Line, Tumor
• Etoposide (pharmacology)
• Female
• Gene Expression Regulation, Leukemic
• Gene Silencing
• HSP90 Heat-Shock Proteins (antagonists & inhibitors, chemistry, metabolism)
• Humans
• Lactams, Macrocyclic (pharmacology, therapeutic use)
• Leukemia, Myeloid (drug therapy, genetics, metabolism)
• Mice
• Mice, SCID
• Proteasome Endopeptidase Complex (metabolism)
• Protein Interaction Domains and Motifs
• Protein Structure, Tertiary
• Triazoles (therapeutic use)
• WT1 Proteins (chemistry, genetics, metabolism)