Inhibition of Rac GTPases in the Therapy of Chronic Myelogenous Leukemia
Annual rept. 1 Apr 2008-31 Mar 2009
CHILDREN'S HOSPITAL MEDICAL CENTER CINCINNATI OH
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Chronic myelogenous leukemia CML is a clonal myeloproliferative disease MPD characterized by the expression of the p210-BCRABL fusion gene 1. This gene is produced by the reciprocal translocation 9 22 q34 q11 that juxtaposes the 3end of Abelson leukemia virus ABL gene with the 5 end of the breakpoint cluster region Bcr gene on chromosome 22. The transcript formed as a result encodes for the BCRABL fusion protein with constitutively active tyrosine kinase activity 2-6. Studies with inducible BCRABL transgenic mice showed that expression of BCRABL in hematopoietic stem cells and progenitors HSCP is required and is sufficient to induce MPD 7. If untreated, chronic phase CP CML patients progress to a poor-prognosis myeloid or lymphoid blastic phase BP. The only curative treatment for CML is allogeneic HSC transplantation. The long-term survival rate for this procedure is approximately 65, however, the procedure is only available to a minority of CML patients due to a lack of compatible donors and age 8-10. Imatinib is an ABL kinase inhibitor that shows significant activity in CP CML and Ph-positive acute leukemias 11. By selective induction of apoptosis of BCRABL-positive cells 12-14, it provides an effective treatment in CML and has rejuvenated the field of rationalized drug design. The selective inhibitory activity of imatinib toward BCRABL has been associated with three problems the emergence of BCRABL mutants in the kinase domain that confer resistance to imatinib the evidence that CML stem cells are the least vulnerable to ABL-targeted therapy and may serve as reservoirs for occult CML progression and the relatively low impact of imatinib therapy on the outcome of BP CML patients 15-18. Resistance to imatinib has an incidence of 4 annually 19.
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