title: Bcl-2 overexpression leads to increases in suppressor of cytokine signaling-3 expression in B cells and de novo follicular lymphoma.
abstract: The t(14;18)(q32;q21), resulting in deregulated expression of B-cell-leukemia/lymphoma-2 (Bcl-2), represents the genetic hallmark in human follicular lymphomas. Substantial evidence supports the hypothesis that the t(14;18) and Bcl-2 overexpression are necessary but not solely responsible for neoplastic transformation and require cooperating genetic derangements for neoplastic transformation to occur. To investigate genes that cooperate with Bcl-2 to influence cellular signaling pathways important for neoplastic transformation, we used oligonucleotide microarrays to determine differential gene expression patterns in CD19+ B cells isolated from Emu-Bcl-2 transgenic mice and wild-type littermate control mice. Fifty-seven genes were induced and 94 genes were repressed by > or =2-fold in Emu-Bcl-2 transgenic mice (P < 0.05). The suppressor of cytokine signaling-3 (SOCS3) gene was found to be overexpressed 5-fold in B cells from Emu-Bcl-2 transgenic mice. Overexpression of Bcl-2 in both mouse embryo fibroblast-1 and hematopoietic cell lines resulted in induction of SOCS3 protein, suggesting a Bcl-2-associated mechanism underlying SOCS3 induction. Immunohistochemistry with SOCS3 antisera on tissue from a cohort of patients with de novo follicular lymphoma revealed marked overexpression of SOCS3 protein that, within the follicular center cell region, was limited to neoplastic follicular lymphoma cells and colocalized with Bcl-2 expression in 9 of 12 de novo follicular lymphoma cases examined. In contrast, SOCS3 protein expression was not detected in the follicular center cell region of benign hyperplastic tonsil tissue. These data suggest that Bcl-2 overexpression leads to the induction of activated signal transducer and activator of transcription 3 (STAT3) and to the induction of SOCS3, which may contribute to the pathogenesis of follicular lymphoma.
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, 333 Cedar Street, WWW-403, Box 208021, New Haven, CT 06520, USA. gary.vanasse@yale.edu
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Vanasse
authors.forename: Robert K
authors.initials: RK
authors.lastname: Winn
authors.forename: Sofya
authors.initials: S
authors.lastname: Rodov
authors.forename: Arthur W
authors.initials: AW
authors.lastname: Zieske
authors.forename: John T
authors.initials: JT
authors.lastname: Li
authors.forename: Joan C
authors.initials: JC
authors.lastname: Tupper
authors.forename: Jingjing
authors.initials: J
authors.lastname: Tang
authors.forename: Elaine W
authors.initials: EW
authors.lastname: Raines
authors.forename: Mette A
authors.initials: MA
authors.lastname: Peters
authors.forename: Ka Yee
authors.initials: KY
authors.lastname: Yeung
authors.forename: John M
authors.initials: JM
authors.lastname: Harlan
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D020868:Gene Silencing / Q000502:physiology; D006801:Humans; D008224:Lymphoma, Follicular / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D014066:Palatine Tonsil / Q000378:metabolism / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012097:Repressor Proteins; C106644:SOCS3 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D014157:Transcription Factors