Unraveling germinal center B cell lymphoma development

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DESCRIPTION (provided by applicant): Lymphomas of SJL and C57L mice are derived from germinal center (GC) B cells and resemble several human GC-derived lymphomas. These mouse and human lymphomas contain CD4+ T cells. The SJL and C57L mouse lymphomas express retroviral superantigen (vSAg29) encoded by endogenous mouse mammary tumor virus (Mtv29), which vigorously stimulates CD4 T cells bearing T cell receptor (TCR) BV16 family. The responding CD4 T cells produce growth factors, upon which the lymphomas depend for their proliferation. The vSAg29 mRNA is produced under the control of a promoter, MMTV envelope transcription activator (META-env), in the envelope region of Mtv29. Demethylation in this promoter region appears to be inevitable for the transcription of vSAg29. This promoter region has a binding site for the zinc-finger transcription factor, Ikaros, and the binding of Ikaros could results in the maintenance of condensed chromatin structure which would leads to transcriptional repression. However, SJL lymphomas over-express a non-DNA binding Ikaros isoform (Ik6) which has a dominant negative effect by relaxing chromatin, and thus permitting access of MMTV-env to transcription factors. Limited profile of gene expression shows that SJL lymphomas express unique set of lymphoma-specific genes. In aim 1, a more extensive analysis will be conducted using an updated mouse GeneChip expression set to find time-dependent progression of gene expression leading to lymphoma, by examining mice at different ages until onset of lymphoma. This study is expected to uncover the sequential genetic events leading to superantigen-driven lymphoma development. A sub-population of human lymphomas express surface CD30, which is a member of the "tumor necrosis factor receptor" family, and CD30 monoclonal antibodies (mAbs) are already in clinical trials for treatment of human lymphomas. However, there is little information on the mechanisms of action and the cellular target of these mAbs. In SJL mice, CD30 mAb blocks lymphoma development in vivo. In aim 2, SJL mice expressing CD30 as a transgene expressed in CD4 T cells, and mice null for either CD30 or for CD30L will be used to understand the mode of action of CD30 mAbs in lymphoma. In aim 3, studies will be conducted using mice transgenic for non-DNA binding isoform of Ikaros, in order to understand the role of Ik6 in lymphoma. The effect of this Ikarose transgene on age-depended induction of vSAg29 and lymphoma development will be examined. This finding is relevant to human lymphoma since the human genome is laden with endogenous retroviral genes (approximately 0.6%), some of which have the potential for transcription.