Role of OCA-B in B cell differentiation and malignancy

描述(申请人提供)：B细胞的分化和功能(抗体产生)是通过特定基因上转录因子的程序化表达和功能来调节的，以响应各种刺激；这些程序和遗传靶点(例如免疫球蛋白[Ig]基因位点)的变化可导致各种恶性肿瘤。B细胞特异性转录辅助激活因子OCA-B通过与启动子结合的OCT因子相互作用激活Ig基因转录的能力被生化鉴定。随后的基因打靶研究表明，OCA-B对于抗原依赖的B细胞分化，包括生发中心(GC)的形成，以及次级Ig亚型的正常表达都是必不可少的，但对于B细胞分化早期的Ig转录来说，OCA-B不是必不可少的。这些观察表明，在早期B细胞中，不仅存在其他(非LG)靶基因，而且还存在另一种依赖于Oct的Ig基因转录的辅助激活因子。OCA-B在GC形成中的关键作用，以及许多起源于GC的淋巴系统恶性肿瘤的存在，突显了了解OCA-B功能和机制的重要性。长期目标是研究OCA-B如何通过不同的靶基因在健康和疾病中调节关键的B细胞分化事件。基于最新的研究进展，结合生物化学、细胞生物学和小鼠基因打靶技术，我们的具体目标是(I)生化纯化和功能鉴定新发现的与OCA-B部分冗余的B细胞特异性OCT辅活化子活性(OCA-B2)；(Ii)通过与一般转录机制和染色质重塑因子的相互作用，详细说明OCA-B在影响Ig启动子和增强子功能及协同作用中的作用机制；(Iii)阐明新发现的非LG OCA-B靶基因在B细胞分化中的作用。(Iv)确定OCA-B的核p34和肉豆蔻酰化质膜/核p35亚型的特定(可能不同的)功能，以及OCA-B/p35响应B细胞受体(BCR)结合的潜在新的细胞质-核信号通路；(V)建立小鼠模型，研究OCA-B在B细胞淋巴瘤中转位的IgH 3‘增强子功能中的作用。

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.