Inhibition of Rac GTPases in the Therapy of Chronic Myelogenous Leukemia
Abstract
Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disease (MPD) characterized by the expression of the p210-BCR/ABL fusion gene [1]. This gene is produced by the reciprocal translocation (9; 22) (q34; q11) that juxtaposes the 3 end 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 BCR/ABL fusion protein with constitutively active tyrosine kinase activity [2-6]. Recent studies with inducible BCR/ABL transgenic mice showed that expression of BCR/ABL in hematopoietic stem cells and progenitors (HSC/P) 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 BCR/ABL-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 BCR/ABL has been associated with three problems: the emergence of BCR/ABL 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. Resistance to imatinib has an incidence of 4% annually.
Document Details
- Document Type
- Technical Report
- Publication Date
- Apr 01, 2008
- Accession Number
- ADA487594
Entities
People
- Jose A Cancelas