Terminal differentiation of chronic myelogenous leukemia cells is induced by targeting of the MUC1-C oncoprotein.

摘要

Chronic myelogenous leukemia (CML) is caused by expression of the Bcr-Abl fusion protein in hematopoietic stem cells. The MUC1-C oncoprotein is expressed in CML blasts and stabilizes Bcr-Abl. The present studies demonstrate that treatment of KU812 and K562 CML cells with GO-201, a cell-penetrating peptide inhibitor of MUC1-C oligomerization, downregulates Bcr-Abl expression and inhibits cell growth. In concert with decreases in Bcr-Abl levels, KU812 and K562 cells responded to GO-201 with induction of a differentiated myeloid phenotype as evidenced by increased expression of CD11b, CD11c and CD14. The results also show that the GO-201-treated cells undergo a late apoptoticecrotic response, consistent with induction of terminal differentiation. Primary CML blasts expressing MUC1 similarly responded to GO-201 with induction of a more differentiated phenotype and late apoptosisecrosis. In addition, treatment of KU812 xenografts in nude mice was associated with upregulation of CD11 and tumor regression. These findings indicate that CML blasts respond to targeting of the MUC1-C oncoprotein with induction of terminal differentiation.