Rac guanosine triphosphatases represent integrating molecular therapeutic targets for BCR-ABL-induced myeloproliferative disease - PubMed (original) (raw)

doi: 10.1016/j.ccr.2007.10.015.

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

Affiliations

Free article

Rac guanosine triphosphatases represent integrating molecular therapeutic targets for BCR-ABL-induced myeloproliferative disease

Emily K Thomas et al. Cancer Cell. 2007 Nov.

Free article

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.

PubMed Disclaimer

Similar articles

Cited by

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources