Role of OCA-B in B cell differentiation and malignancy

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DESCRIPTION (provided by applicant): B cell differentiation and function (antibody production) is regulated through the programmed expression and function of transcription factors on specific genes in response to various stimuli; and alterations in these programs and in the genetic targets (e.g. immunoglobulin [Ig] gene loci) can lead to various malignancies. The B cell-specific transcriptional coactivator OCA-B was identified biochemically on the basis of its ability to activate Ig gene transcription through interactions with promoter-bound OCT factors. Subsequent gene targeting studies showed that OCA-B is essential both for antigen-dependent B cell differentiation, including germinal center (GC) formation, and for normal expression of secondary Ig isotypes, but not for Ig transcription in early B cell differentiation. These observations suggested the presence not only of other (non-lg) target genes but also of another coactivator for OCT-dependent transcription of Ig genes in early B cells. The critical role of OCA-B in GC formation, along with the presence of many lymphoid malignancies of GC origin, underscores the importance of understanding OCA-B functions and mechanisms. The long-term objective is to study how OCA-B regulates critical B cell differentiation events, through different target genes, in health and disease. Based on recent developments, and using integrated biochemical, cell biological and mouse gene targeting approaches, our specific objectives are (i) to biochemically purify and functionally characterize a newly-identified B cell-specific OCT coactivator activity (OCA-B2) that could be partially redundant with OCA-B, (ii) to detail the mechanism of action of OCA-B, through interactions with the general transcriptional machinery and chromatin remodeling factors, in effecting Ig promoter and enhancer function and synergy, (iii) to elucidate the role of newly identified non-lg OCA-B target genes in B cell differentiation, (iv) to determine the specific (potentially distinct) functions of the nuclear p34 and myristoylated plasma membrane/nuclear p35 isoforms of OCA-B, as well as a potentially novel cytoplasmic-nuclear signaling pathway for OCA-B/p35 in response to B cell receptor (BCR) engagement and (v) to develop a mouse model to investigate the role of OCA-B in the function of the translocated IgH 3' enhancer in B cell lymphomas.