Author/Authors :
Thomas، نويسنده , , Emily K. and Cancelas، نويسنده , , Jose A. and Chae، نويسنده , , Hee-Don and Cox، نويسنده , , Adrienne D. and Keller، نويسنده , , Patricia J. and Perrotti، نويسنده , , Danilo and Neviani، نويسنده , , Paolo and Druker، نويسنده , , Brian J. and Setchell، نويسنده , , Kenneth D.R. and Zheng، نويسنده , , Yi and Harris، نويسنده , , Chad E. and Williams، نويسنده , , David A.، نويسنده ,
Abstract :
Summary
c 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.
