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.
journal_name
Cancer Celljournal_title
Cancer cellauthors
Thomas EK,Cancelas JA,Chae HD,Cox AD,Keller PJ,Perrotti D,Neviani P,Druker BJ,Setchell KD,Zheng Y,Harris CE,Williams DAdoi
10.1016/j.ccr.2007.10.015subject
Has Abstractpub_date
2007-11-01 00:00:00pages
467-78issue
5eissn
1535-6108issn
1878-3686pii
S1535-6108(07)00300-5journal_volume
12pub_type
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