Li Yin, Rehan Ahmad, Michio Kosugi, Takeshi Kawano, David Avigan, Richard Stone, Surender Kharbanda and Donald W. Kufe

Li Yin

Dana-Farber Cancer Institute, Boston, Massachusetts

Rehan Ahmad

Dana-Farber Cancer Institute Harvard Medical School Boston, MA 02115

Michio Kosugi

Dana-Farber Cancer Institute, Boston, Massachusetts

Takeshi Kawano

Dana-Farber Cancer Institute, Boston, Massachusetts

David Avigan

Beth Israel Deaconess Medical Center, Harvard Medical School Boston, MA

Richard Stone

Dana-Farber Cancer Institute, Boston, MA

Surender Kharbanda

Dana-Farber Cancer Institute Harvard Medical School Boston, MA 02115

Donald W. Kufe

Corresponding author: Donald_Kufe@dfci.harvard.edu
Dana-Farber Cancer Institute Harvard Medical School Boston, MA 02115

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 apoptotic/necrotic 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 apoptosis/necrosis. 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.