title: SET oncoprotein overexpression in B-cell chronic lymphocytic leukemia and non-Hodgkin lymphoma: a predictor of aggressive disease and a new treatment target.
abstract: 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.
authors.affiliation: Oncotide Pharmaceuticals, Durham, NC, USA. dchristensen@oncotide.com
authors.forename: Dale J
authors.initials: DJ
authors.lastname: Christensen
authors.forename: Youwei
authors.initials: Y
authors.lastname: Chen
authors.forename: Jessica
authors.initials: J
authors.lastname: Oddo
authors.forename: Karen M
authors.initials: KM
authors.lastname: Matta
authors.forename: Jessica
authors.initials: J
authors.lastname: Neil
authors.forename: Evan D
authors.initials: ED
authors.lastname: Davis
authors.forename: Alicia D
authors.initials: AD
authors.lastname: Volkheimer
authors.forename: Mark C
authors.initials: MC
authors.lastname: Lanasa
authors.forename: Daphne R
authors.initials: DR
authors.lastname: Friedman
authors.forename: Barbara K
authors.initials: BK
authors.lastname: Goodman
authors.forename: Jon P
authors.initials: JP
authors.lastname: Gockerman
authors.forename: Louis F
authors.initials: LF
authors.lastname: Diehl
authors.forename: Carlos M
authors.initials: CM
authors.lastname: de Castro
authors.forename: Joseph O
authors.initials: JO
authors.lastname: Moore
authors.forename: Michael P
authors.initials: MP
authors.lastname: Vitek
authors.forename: J Brice
authors.initials: JB
authors.lastname: Weinberg
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D056488:Histone Chaperones / Q000819:agonists* / Q000096:biosynthesis*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010455:Peptides / Q000494:pharmacology*; D054648:Protein Phosphatase 2 / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D014157:Transcription Factors / Q000819:agonists* / Q000096:biosynthesis*; D023041:Xenograft Model Antitumor Assays
chemical_list: D004268:DNA-Binding Proteins; D056488:Histone Chaperones; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; C583613:OP449 peptide; D010455:Peptides; D019253:Proto-Oncogene Proteins c-bcl-2; C513473:SET protein, human; D014157:Transcription Factors; D054648:Protein Phosphatase 2