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

Abstract
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.
AuthorsLi Yin, Rehan Ahmad, Michio Kosugi, Takeshi Kawano, David Avigan, Richard Stone, Surender Kharbanda, Donald Kufe
JournalCancer biology & therapy (Cancer Biol Ther) Vol. 10 Issue 5 Pg. 483-91 (Sep 01 2010) ISSN: 1555-8576 [Electronic] United States
PMID20592495 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Comment)
Chemical References
  • Antineoplastic Agents
  • CD11 Antigens
  • CD11b Antigen
  • CD11c Antigen
  • GO 201
  • Lipopolysaccharide Receptors
  • Mucin-1
  • Peptides
  • Fusion Proteins, bcr-abl
Topics
  • Animals
  • Antineoplastic Agents (pharmacology)
  • Apoptosis (genetics)
  • CD11 Antigens (analysis)
  • CD11b Antigen (analysis)
  • CD11c Antigen (analysis)
  • Cell Differentiation
  • Cell Line, Tumor
  • Fusion Proteins, bcr-abl (genetics, metabolism)
  • Humans
  • Immunoblotting
  • K562 Cells
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy, genetics, metabolism, pathology)
  • Lipopolysaccharide Receptors
  • Mice
  • Mice, Inbred BALB C
  • Molecular Targeted Therapy
  • Mucin-1 (chemistry, genetics, metabolism)
  • Myelopoiesis
  • Peptides (pharmacology)
  • Protein Multimerization
  • Protein Transport

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