The goal of this work is to elucidate molecular mechanisms which regulate immunoglobulin gene transcription in B-lymphocytes. This information is important for understanding the processes involved in control of normal cell growth and development. It will also increase our understanding of disease states in which these regulatory mechanisms are defective such as loss of growth control in leukemias and lymphomas and lack of normal development in immune deficiency diseases. The proposal is divided into three parts. In the first part, DNA sequences, soluble regulatory molecules and alterations in chromatin structure which may affect immunoglobulin gene transcription during B-cell maturation will be studied. The transcriptional enhancer region which our group has recently discovered between Jh and CMu in the heavy chain locus will be fully characterized. In addition, vector/cell culture systems will be developed and used to study transcription of cloned immunoglobulin genes introduced into various types of animal cells including murine B cells. The second section focuses on analysis of how translocation to the immunoglobulin heavy chain locus alters the amount and content of c-myc oncogene transcripts in murine plasmacytomas and how this event may be related to oncogenesis. After the differences in c-myc transcripts are elucidated, altered DNA sequences, chromatin structure and other factors which may be responsible for altered oncogene expression will be analyzed. The final series of experiments deals with development of an in vitro system for suppression of antibody protein synthesis in S107 plasmacytoma cells by antiidiotype T suppressor cells. This system will allow the mechanism responsible for B-cell suppression to be analyzed at a molecular level.
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