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

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 T Swords, Gail E. Tomlinson, Minoo Battiwalla, Francis J. Giles, Kelvin P. Lee, Swaminathan Padmanabhan

Research output: Contribution to journalArticle

28 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)4591-4599
Number of pages9
JournalBlood
Volume116
Issue number22
DOIs
StatePublished - Nov 25 2010
Externally publishedYes

Fingerprint

HSP90 Heat-Shock Proteins
Myeloid Leukemia
Wilms Tumor
Tumors
Proteins
Cell Survival
Leukemia
Chemotherapy
tanespimycin
Proto-Oncogene Proteins c-bcl-2
Cells
Proto-Oncogene Proteins c-myc
Drug Therapy
Ubiquitination
Proteasome Endopeptidase Complex
RNA Interference
Heterografts
Disease-Free Survival

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Bansal, H., Bansal, S., Rao, M., Foley, K. P., Sang, J., Proia, D. A., ... Padmanabhan, S. (2010). Heat shock protein 90 regulates the expression of Wilms tumor 1 protein in myeloid leukemias. Blood, 116(22), 4591-4599. https://doi.org/10.1182/blood-2009-10-247239

Heat shock protein 90 regulates the expression of Wilms tumor 1 protein in myeloid leukemias. / 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 T; Tomlinson, Gail E.; Battiwalla, Minoo; Giles, Francis J.; Lee, Kelvin P.; Padmanabhan, Swaminathan.

In: Blood, Vol. 116, No. 22, 25.11.2010, p. 4591-4599.

Research output: Contribution to journalArticle

Bansal, H, Bansal, S, Rao, M, Foley, KP, Sang, J, Proia, DA, Blackman, RK, Ying, W, Barsoum, J, Baer, MR, Kelly, K, Swords, RT, Tomlinson, GE, Battiwalla, M, Giles, FJ, Lee, KP & Padmanabhan, S 2010, 'Heat shock protein 90 regulates the expression of Wilms tumor 1 protein in myeloid leukemias', Blood, vol. 116, no. 22, pp. 4591-4599. https://doi.org/10.1182/blood-2009-10-247239
Bansal H, Bansal S, Rao M, Foley KP, Sang J, Proia DA et al. Heat shock protein 90 regulates the expression of Wilms tumor 1 protein in myeloid leukemias. Blood. 2010 Nov 25;116(22):4591-4599. https://doi.org/10.1182/blood-2009-10-247239
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 T ; Tomlinson, Gail E. ; Battiwalla, Minoo ; Giles, Francis J. ; Lee, Kelvin P. ; Padmanabhan, Swaminathan. / Heat shock protein 90 regulates the expression of Wilms tumor 1 protein in myeloid leukemias. In: Blood. 2010 ; Vol. 116, No. 22. pp. 4591-4599.
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