Journal
LEUKEMIA
Volume 22, Issue 5, Pages 898-904Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2008.71
Keywords
Rac GTPases; chronic myelogenous leukemia; BCR-ABL; imatinib
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Funding
- NHLBI NIH HHS [P01 HL069974, HL69974] Funding Source: Medline
- NICHD NIH HHS [T32 HD046387] Funding Source: Medline
- NIDDK NIH HHS [R01 DK062757] Funding Source: Medline
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Chronic myelogenous leukemia (CML) is a malignant disease characterized by expression of p210-BCR-ABL, the product of the Philadelphia chromosome. Survival of CML patients has been significantly improved with the introduction of tyrosine kinase inhibitors that induce long-term hematologic remissions. However, mounting evidence indicates that the use of a single tyrosine kinase inhibitor does not cure this disease due to the persistence of p210-BCR-ABL at the molecular level or the acquired resistance in the stem cell compartment to individual inhibitors. We have recently shown in a murine model that deficiency of the Rho GTPases Rac1 and Rac2 significantly reduces p210-BCR-ABL-mediated proliferation in vitro and myeloproliferative disease in vivo, suggesting Rac as a potential therapeutic target in p210-BCR-ABL-induced disease. This target has been further validated using a first-generation Rac-specific small molecule inhibitor. In this review we describe the role of Rac GTPases in p210-BCR-ABL-induced leukemogenesis and explore the possibility of combinatorial therapies that include tyrosine kinase inhibitor(s) and Rac GTPase inhibitors in the treatment of CML.
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