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Repression of B-Cell Linker (BLNK) and B-Cell Adaptor for Phosphoinositide 3-Kinase (BCAP) Is Important for Lymphocyte Transformation by Rel Proteins

¹ Center for Advanced Biotechnology and Medicine, ² Graduate Program in Biochemistry and Molecular Biology, and ³ Department of Biochemistry, Robert Wood Johnson Medical School; ⁴ BioMAPS Institute for Quantitative Biology, Rutgers University, Piscataway, New Jersey; ⁵ Fred Hutchinson Cancer Research Center, Seattle, Washington; and ⁶ sanofi-aventis, Bridgewater, New Jersey

Requests for reprints: Céline Gélinas, CABM, 679 Hoes Lane, Piscataway, NJ 08854. Phone: 732-235-5035; Fax: 732-235-4466; E-mail: gelinas{at}cabm.rutgers.edu.

Key Words: Rel • NF-B • transformation • BLNK • BCAP

Persistent Rel/nuclear factor-B (NF-B) activity is a hallmark of many human cancers, and the Rel proteins are implicated in leukemia/lymphomagenesis but the mechanism is not fully understood. Microarray analysis to identify transformation-impacting genes regulated by NF-B's oncogenic v-Rel and c-Rel proteins uncovered that Rel protein expression leads to transcriptional repression of key B-cell receptor (BCR) components and signaling molecules like B-cell linker (BLNK), the B-cell adaptor for phosphoinositide 3-kinase (BCAP) and immunoglobulin light chain (Ig), and is accompanied by a block in BCR-mediated activation of extracellular signal-regulated kinase, Akt, and c-Jun-NH₂-kinase in response to anti-IgM. The BLNK and BCAP proteins were also down-regulated in lymphoid cells expressing a transformation-competent chimeric RelA/v-Rel protein, suggesting a correlation with the capacity of Rel proteins to transform lymphocytes. DNA-binding studies identified functional NF-B–binding sites, and chromatin immunoprecipitation (ChIP) data showed binding of Rel to the endogenous blnk and bcap promoters in vivo. Importantly, restoration of either BLNK or BCAP expression strongly inhibited transformation of primary chicken lymphocytes by the potent NF-B oncoprotein v-Rel. These findings are interesting because blnk and other BCR components and signaling molecules are down-regulated in primary mediastinal large B-cell lymphomas and Hodgkin's lymphomas, which depend on c-Rel for survival, and are consistent with the tumor suppressor function of BLNK. Overall, our results indicate that down-regulation of BLNK and BCAP is an important contributing factor to the malignant transformation of lymphocytes by Rel and suggest that gene repression may be as important as transcriptional activation for Rel's transforming activity. [Cancer Res 2008;68(3):808–14]

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