Rac Guanosine Triphosphatases Represent Integrating Molecular Therapeutic Targets for BCR-ABL-Induced Myeloproliferative Disease

Emily K. Thomas, Jose A. Cancelas, Hee Don Chae, Adrienne D. Cox, Patricia J. Keller, Danilo Perrotti, Paolo Neviani, Brian J. Druker, Kenneth D.R. Setchell, Yi Zheng, Chad E. Harris, David A. Williams

Research output: Contribution to journalArticle

122 Scopus citations

Abstract

Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disease (MPD) initiated by expression of the p210-BCR-ABL fusion protein. We demonstrate in a murine model of p210-BCR-ABL-induced MPD that gene targeting of Rac1 and Rac2 significantly delays or abrogates disease development. Attenuation of the disease phenotype is associated with severely diminished p210-BCR-ABL-induced downstream signaling in primary hematopoietic cells. We utilize NSC23766, a small molecule antagonist of Rac activation, to validate biochemically and functionally Rac as a molecular target in both a relevant animal model and in primary human CML cells in vitro and in a xenograft model in vivo, including in Imatinib-resistant p210-BCR-ABL disease. These data demonstrate that Rac is an additional therapeutic target in p210-BCR-ABL-mediated MPD.

Original languageEnglish (US)
Pages (from-to)467-478
Number of pages12
JournalCancer Cell
Volume12
Issue number5
DOIs
StatePublished - Nov 13 2007

Keywords

  • CELLCYCLE

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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    Thomas, E. K., Cancelas, J. A., Chae, H. D., Cox, A. D., Keller, P. J., Perrotti, D., Neviani, P., Druker, B. J., Setchell, K. D. R., Zheng, Y., Harris, C. E., & Williams, D. A. (2007). Rac Guanosine Triphosphatases Represent Integrating Molecular Therapeutic Targets for BCR-ABL-Induced Myeloproliferative Disease. Cancer Cell, 12(5), 467-478. https://doi.org/10.1016/j.ccr.2007.10.015