Kenneth Wright, PhD

My primary interest is the molecular mechanisms controlling genes involved in antigen presentation. Antigen presentation is a key step in eliciting a normal immune response and it can play an important role in tumor rejection and autoimmunity. The laboratory is currently focused on two transcription factors, CIITA and PRDI-BF1. CIITA is a transcriptional activator and master regulator of the MHC Class II family of antigen presentation genes. PRDI-BF1 is a transcriptional repressor that silences CIITA and promotes terminal differentiation of immune cells. We are examining these factors in the two primary cell types. The first is in B-lymphocytes and during their terminal differentiation into antibody secreting plasma cells. The second is in primary human and mouse dendritic cells. In B-lymphocytes our laboratory has previously mapped the B-cell specific promoter of CIITA. This was done through a combination of in vivo and in vitro DNA binding studies. One of the more significant outcomes of this study was the discovery that the transcriptional silencer PRDI-BF1 down-regulates CIITA and MHC class II expression in multiple myeloma cells. Multiple myeloma is a disease of malignant plasma cells. PRDI-BF1 also down-regulates c-myc, Pax5 and interferon-beta expression. The chromosomal location of PRDI-BF1, 6q21, is deleted in a high percentage of B cell lymphomas as well as other types of cancer. Our investigations have identified a natural truncated form of PRDI-BF1 that is lacking a critical N-terminal domain in multiple myeloma cells and have shown that this isoform is impaired in repressing CIITA transcription. Deletion of this domain from the other two PRDI-BF1 family members converts these proteins from growth suppressive to oncogenic. The role of PRDI-BF1 and its truncated form in the development and progression of multiple myeloma is currently under investigation. We are also characterizing the dendritic cell specific promoter of CIITA in both human and mouse primary dendritic cells. CIITA transcription is high in immature DC cells but is rapidly turned off when the cells receive a maturation signal. We have identified several key transcription factors required for DC expression. The role of these factors as well as the silencing of expression observed upon dendritic cell maturation is an area of continued investigation using multiple approaches including gene knock-out mouse models. These studies will provide vital information for targeting expression of tumor specific antigens directly to the professional antigen presenting dendritic cell with out altering expression in other cells. The mechanism of action of PRDI-BF1 is also being studied. PRDI-BF1 is known to recruit histone deacetylases as part of its transcription repression activity. We have now identified that specific histone methyltransferases are also recruited by PRDI-BF1 and play an important role in its repression activity. This indicates that PRDI-BF1 may serve as a scaffold molecule to bring multiple chromatin modifying enzymes to specific promoters such as CIITA. Investigations are continuing to dissect the role of the histone methyltransferases and PRDI-BF1 in myeloma, lymphoma and dendritic cell development. In addition, a small molecule inhibitor screen is ongoing to identify compounds that interrupt histone methyltransferase activity as potential therapeutics in the treatment of myeloma and lymphoma.