The SWI/SNF protein PBRM1 restrains VHL-loss-driven clear cell renal cell carcinoma Journal Article


Authors: Nargund, A. M.; Pham, C. G.; Dong, Y.; Wang, P. I.; Osmangeyoglu, H. U.; Xie, Y.; Aras, O.; Han, S.; Oyama, T.; Takeda, S.; Ray, C. E.; Dong, Z.; Berge, M.; Hakimi, A. A.; Monette, S.; Lekaye, C. L.; Koutcher, J. A.; Leslie, C. S.; Creighton, C. J.; Weinhold, N.; Lee, W.; Tickoo, S. K.; Wang, Z.; Cheng, E. H.; Hsieh, J. J.
Article Title: The SWI/SNF protein PBRM1 restrains VHL-loss-driven clear cell renal cell carcinoma
Abstract: PBRM1 is the second most commonly mutated gene after VHL in clear cell renal cell carcinoma (ccRCC). However, the biological consequences of PBRM1 mutations for kidney tumorigenesis are unknown. Here, we find that kidney-specific deletion of Vhl and Pbrm1, but not either gene alone, results in bilateral, multifocal, transplantable clear cell kidney cancers. PBRM1 loss amplified the transcriptional outputs of HIF1 and STAT3 incurred by Vhl deficiency. Analysis of mouse and human ccRCC revealed convergence on mTOR activation, representing the third driver event after genetic inactivation of VHL and PBRM1. Our study reports a physiological preclinical ccRCC mouse model that recapitulates somatic mutations in human ccRCC and provides mechanistic and therapeutic insights into PBRM1 mutated subtypes of human ccRCC. © 2017 The Author(s)
Keywords: genetics; epigenetics; kidney cancer; mtor; stat3; vhl; pbrm1; ccrcc; hif1; mouse tumor model
Journal Title: Cell Reports
Volume: 18
Issue: 12
ISSN: 2211-1247
Publisher: Cell Press  
Date Published: 2017-03-21
Start Page: 2893
End Page: 2906
Language: English
DOI: 10.1016/j.celrep.2017.02.074
PROVIDER: scopus
PUBMED: 28329682
PMCID: PMC5431084
DOI/URL:
Notes: Article -- Export Date: 2 May 2017 -- Source: Scopus
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MSK Authors
  1. Satish K Tickoo
    483 Tickoo
  2. Hongbiao Carl Lekaye
    32 Lekaye
  3. Jason A Koutcher
    278 Koutcher
  4. Sebastien Monette
    149 Monette
  5. Yiyu Dong
    26 Dong
  6. Shugaku Takeda
    18 Takeda
  7. Emily H Cheng
    78 Cheng
  8. Christina Leslie
    188 Leslie
  9. Amrita Mohan Nargund
    12 Nargund
  10. Toshinao Oyama
    6 Oyama
  11. Can Gia Pham
    8 Pham
  12. William Lee
    39 Lee
  13. Abraham Ari Hakimi
    324 Hakimi
  14. Omer Aras
    75 Aras
  15. Patricia Ibai Wang
    12 Wang
  16. Song   Han
    9 Han
  17. Yuchen Xie
    6 Xie
  18. Chelsea Elizabeth Ray
    2 Ray
  19. Zhenghong Dong
    1 Dong
  20. Mathieu Berge
    1 Berge