TCL1 Oncogene in B Lymphocyte Development and Neoplasia

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DESCRIPTION (provided by applicant): Most lymphoid malignancies arise by transformation of germinal center (GC) experienced B cells. In the initial funded period we showed that the TCL1 protooncogene was abnormally expressed in samples from the three major GC B cell lymphoma categories. Our Original Specific Aims addressed the main hypothesis that abnormal TCL1 expression had an active rather than a passive role in transforming GC B cells. We successfully completed these Aims by providing (1) a first analysis of TCL1 transcriptional control, (2) a TCL1 transgenic model that developed tumors strongly resembling human GC B cell lymphomas, and (3) a compendium of key genetic and epigenetic changes in TCL1-initiated GC B cell malignancies. In this competitive renewal, we build on these successes with three New Specific Aims that focus on the detailed mechanism(s) regulating TCL1 in GC B cells and dysregulating TCL1 in GC B cell lymphomas. Based on an initiating role for TCL1 in B lymphomagenesis, we predict that correcting dysregulated TCL1 expression will impede malignant degeneration. Further supporting a causative role for TCL1 in GC B cell transformation is the observation that 60 to 100% of follicular (FL), Burkitt (BL) and diffuse large B cell (DLBCL) lymphomas show dysregulated TCL1 levels. Recent work has revealed a role for robust, aberrant TCL1 expression in the pathogenesis and molecular diagnosis of human BL. We have also shown that TCL1 specifically augments both PI3K and PKC signaling pathways known to control B cell proliferation and survival. Therefore, Specific Aim 1 determines the regulatory mechanisms in transformed GC B cell lines that promote abnormal TCL1 expression as reasonable representations of similar mechanisms that control dysregulated expression in vivo. Specific Aim 2 identifies the normal regulatory program that controls stage- specific TCL1 expression in primary human B cells for comparisons with mechanisms of TCL1 dysregulation. Specific Aim 3 uses manipulations of the TCL1 transcriptional activator and repressor linked pathways identified in Aims 1 and 2 to assess the effects on proliferation and survival of TCL1-altered GC B cells and GC B cell lymphomas. Our studies incorporate IRB-approved and characterized patient samples and isolated primary B cells to provide clinically relevant insights into the pathogenesis of GC B cell lymphomas by controlling TCL1 protooncogene expression for potential therapeutic interventions.