Effects of Inactivating Ras-Converting Enzyme or Isoprenylcysteine Carboxyl Methyltransferases in the Pathogenesis of Chronic Myelogenous Leukemia

Abstract : The BCR-ABL fusion gene, the hallmark of CML, plays a causal role in the development of CML. The BCR-ABL tyrosine kinase inhibitors have been successfully used to treat patients with CML, but residual disease persists and drug resistance emerges. Although BCR-ABL remains to be an attractive target for developing CML therapies, identifying and targeting additional essential components in the development of CML are important for overcoming resistance to BCR-ABL tyrosine kinase inhibitors and for eradicating leukemic cells. Substantial evidence indicates that Ras and Ras related proteins are critical mediators of BCR-ABL in leukemogenesis. Ras-converting enzyme (Rce1) and isoprenylcysteine carboxyl methyltransferase (Icmt) are two unique enzymes for Ras modifications that are critical for their functions. Targeted inactivation of Rce1 or Icmt is, therefore, an attractive strategy for the treatment of CML. The goal of this project is to determine whether targeted inactivation of Rce1 or Icmt could block BCR-ABL leukemogenesis. In this study, we have found that Icmt plays a critical role in BCR-ABL leukemogenesis and that the role of Rce1 in BCR-ABL leukemogenesis is dosage dependent. We have also found that the mutation affecting the AAX peptide cleavage and methylation of RAS in cis significantly reduces RAS leukemogenesis, suggesting that the AAX peptide cleavage and methylation play an important role for RAS leukemogenesis.