The Proteasome as a Therapeutic Target in Chronic Myeloid Leukemia

Abstract

Chronic Myeloid Leukemia (CML) appears as a consequence of the reciprocal translocation between chromosomes 9 and 22 which results in the expression of the Bcr-Abl oncoprotein in a hematopoietic stem cell. The tyrosine kinase activity of Bcr-Abl is the direct cause of the disease. Therefore, inhibitors of this kinase activity are being used in the treatment of CML. Imatinib was the first of such inhibitors and is the first line treatment in CML. However, the appearance of Bcr-Abl mutants that are resistant to these inhibitors has emerged as a problem in the treatment of CML. Consequently, the search for new drugs or therapeutic targets is underway. The proteasome is a multiprotein complex where proteins are degraded in a much regulated manner. Protein degradation at the proteasome is dependent upon ubiquitylation, which, in turn, is mediated by ubiquitin-ligase complexes. By degrading specific proteins, the proteasome is involved in cellular processes as important as cell cycle regulation, proliferation, differentiation and survival. As such, its activity is also related to the transformation of tumor cells. In fact, it has been shown that tumor cells show an increase in proteasome activity. Specifically, Bcr-Abl tyrosine kinase activity results in an increase of proteasome activity and degradation of some negative regulators of cell cycle progression as p27kip1. Therefore, proteasome inhibitors could be an alternative in CML treatment. In this chapter, we will discuss the available data suggesting that proteasome inhibition could be used in the treatment of CML, including those cases in which Bcr-Abl inhibition is not a possibility.