SET oncoprotein overexpression in B-cell chronic lymphocytic leukemia and non-Hodgkin lymphoma: a predictor of aggressive disease and a new treatment target
| Autor: | Jessica Neil, Michael P. Vitek, J. Brice Weinberg, Carlos M. de Castro, Evan D. Davis, Alicia D. Volkheimer, Youwei Chen, Louis F. Diehl, Jon P. Gockerman, Dale J. Christensen, Jessica Oddo, Daphne R. Friedman, Joseph O. Moore, Barbara K. Goodman, Mark C. Lanasa, Karen M. Matta |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Male
Clinical Trials and Observations Chronic lymphocytic leukemia Immunology Mice SCID Biology Biochemistry Mice BCL9 immune system diseases Cell Line Tumor hemic and lymphatic diseases medicine Animals Humans Cytotoxic T cell Histone Chaperones Protein Phosphatase 2 neoplasms Gene Expression Regulation Leukemic Lymphoma Non-Hodgkin Cancer Cell Biology Hematology medicine.disease Leukemia Lymphocytic Chronic B-Cell Xenograft Model Antitumor Assays Lymphoma DNA-Binding Proteins Myeloid Cell Leukemia Sequence 1 Protein Leukemia Proto-Oncogene Proteins c-bcl-2 Apoptosis Cancer research Peptides Transcription Factors |
| Zdroj: | Blood. 118:4150-4158 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2011-04-351072 |
| Popis: | B-cell chronic lymphocytic leukemia (CLL), an incurable leukemia, is characterized by defective apoptosis. We found that the SET oncoprotein, a potent inhibitor of the protein phosphatase 2A (PP2A) tumor suppressor, is overexpressed in primary CLL cells and B-cell non-Hodgkin lymphoma (NHL) cell line cells. In CLL, increased levels of SET correlated significantly with disease severity (shorter time to treatment and overall survival). We developed SET antagonist peptides that bound SET, increased cellular PP2A activity, decreased Mcl-1 expression, and displayed selective cytotoxicity for CLL and NHL cells in vitro. In addition, shRNA for SET was cytotoxic for NHL cells in vitro. The SET antagonist peptide COG449 inhibited growth of NHL tumor xenografts in mice. These data demonstrate that SET is a new treatment target in B-cell malignancies and that SET antagonists represent novel agents for treatment of CLL and NHL. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|