The fact that Bcr-Abl kinase activity is central to its transforming potency has served as the rationale for the development of imatinib for therapy of Bcr-Abl positive leukemias. There is some evidence that targeting the kinase activity may have limitations. Some biological effects of Bcr-Abl are not kinase dependent, including effects on migration and adhesion (19). While these effects obviously do not prevent imatinib from inducing responses, it remains possible that they contribute to the persistence of minimal residual disease. Thus, eliminating these cells would require agents that target the Bcr-Abl protein rather than its kinase activity. Compounds with this activity include geldanamycin derivatives, which inhibit heat-shock protein 90 (HSP90), a molecular chaperone required for Bcr-Abl stability (45), LAQ824, a histone deacetylase inhibitor (46), and arsenic trioxide (47). Another possibility is that, the survival of primitive CML stem cells is independent of Bcr-Abl, relying on physiological signals provided by the bone marrow microenvironment or cytokines. If this were the case, then neither inhibiting Bcr-Abl kinase activity nor eliminating the protein would be sufficient to eradicate residual leukemia (48). However, Bcr-Abl could still serve as a specific immunological target. In fact, Bcr-Abl junction peptides are processed by and expressed by CML mononuclear cells (49). This opens the possibility of developing vaccines to specifically target leukemia cells.
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