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Cancer Genes and Genomics

Bcl-2 Overexpression Leads to Increases in Suppressor of Cytokine Signaling-3 Expression in B Cells and De novo Follicular Lymphoma¹

Departments of ¹ Internal Medicine and ² Laboratory Medicine, Yale University School of Medicine, New Haven, Connecticut and Departments of ³ Internal Medicine, ⁴ Surgery, and ⁵ Pathology, School of Medicine, and ⁶ Center for Expression Arrays, University of Washington, Seattle, Washington

Requests for reprints: Gary J. Vanasse, Section of Hematology, Department of Internal Medicine, Yale University School of Medicine, 333 Cedar Street, WWW-403, Box 208021, New Haven, CT 06520. Phone: 203-737-2340; Fax: 203-785-7232. E-mail: gary.vanasse{at}yale.edu

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 Eµ-Bcl-2 transgenic mice and wild-type littermate control mice. Fifty-seven genes were induced and 94 genes were repressed by 2-fold in Eµ-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 Eµ-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.

Key Words: Bcl-2 • SOCS3 gene • follicular lymphoma • microarray • B cells

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