Terminal differentiation of chronic myelogenous leukemia cells is induced by targeting of the MUC1-C oncoprotein.
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.
Yin
Li
L
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Ahmad
Rehan
R
Kosugi
Michio
M
Kawano
Takeshi
T
Avigan
David
D
Stone
Richard
R
Kharbanda
Surender
S
Kufe
Donald
D
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000235:genetics; D018845:CD11 Antigens / Q000032:analysis; D039481:CD11b Antigen / Q000032:analysis; D039521:CD11c Antigen / Q000032:analysis; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D018950:Lipopolysaccharide Receptors; D051379:Mice; D008807:Mice, Inbred BALB C; D058990:Molecular Targeted Therapy; D018396:Mucin-1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D038042:Myelopoiesis; D010455:Peptides / Q000494:pharmacology*; D055503:Protein Multimerization; D021381:Protein Transport
D000970:Antineoplastic Agents; D018845:CD11 Antigens; D039481:CD11b Antigen; D039521:CD11c Antigen; C549568:GO 201; D018950:Lipopolysaccharide Receptors; D018396:Mucin-1; D010455:Peptides; D016044:Fusion Proteins, bcr-abl