Regulation of B Cell Identity and Lineage Progression

B 细胞身份和谱系进展的调节

• 批准号: 7917958
• 负责人: James R. Hagman
• 金额: $ 39万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7917958
• 关键词: Address; Alleles; Antibodies; Autoimmune Diseases; B-Cell Development; B-Lymphocytes; Bone Marrow; CD19 gene; Cell Lineage; Cells; DNA Sequence Rearrangement; Defect; Development; Exhibits; Gene Expression; Gene Rearrangement; Gene Targeting; Genes; Genetic Transcription; Hematopoietic; Immunoglobulin Genes; Immunoglobulins; Knock-out; Knockout Mice; Laboratories; Light; Maintenance; Malignant Neoplasms; Measures; Mediator of activation protein; Molecular; Mus; Mutate; Natural Killer Cells; Normal Cell; Phenotype; Process; Production; Proteins; Regulation; Relative (related person); Role; Signal Transduction; Staging; Testing; Transcription Repressor/Corepressor; Transgenes; V(D)J Recombination; base; dosage; insight; mutant; pathogen; prevent; progenitor; public health relevance; response; transcription factor

DESCRIPTION (provided by applicant): EBF1 is a crucial regulator of B lymphocyte lineage specification and commitment. In mice lacking EBF1 (encoded by the Ebf1 gene), B cell development is arrested and immunoglobulins (Ig) are not produced. Recently, we determined that mice with a single wild type Ebf1 allele (Ehet mice) exhibit defects in B cell development in the bone marrow. B cell development is further impaired in Ehet mice that also possess a single functional Runx1 (Rhet) allele. Runx1 encodes the Runt domain transcription factor Runx1 (CBF12/PEBP21), a functional partner of EBF1. In single Ehet and double (ERhet) haploinsufficient mice, we observed 1) substantially decreased numbers of CD19+ cells in the bone marrow, 2) delayed activation of pre-B cell markers, 3) reduced levels of Ig; light (L) chain rearrangements and 4) the loss of B cell identity, as evidenced by the mixing of B cell and NK cell phenotypes. The loss of B cell identity occurred in the presence of Pax5, a defined mediator of B cell commitment. We will address the central hypothesis that EBF1 is a primary regulator of B cell lineage specification and commitment. We propose that 1) the appropriate dosage of EBF1 is critical for establishing B cell identity and progression, and 2) this role of EBF1 is dependent on its functions as a transcriptional repressor, which is an undefined mechanism. We will continue our studies by identifying signaling defects in pro-B/pre-B cells that express reduced levels of EBF1. In the last aim, we will address whether EBF1 is required for the maintenance of B cell identity by utilizing new Ebf1 conditional knockout (Ecko) mice developed in our laboratory. Together, these studies will result in important new insights concerning functions of EBF1 in the regulation of B cell lineage specification, commitment and progression. PUBLIC HEALTH RELEVANCE: Early B cell Factor (EBF1) is essential for the production of B lymphocytes, which produce antibodies in response to foreign pathogens. Here, we will determine how EBF1 regulates the development of these cells in bone marrow. We will also address how EBF prevents the expression of genes of other types of hematopoietic cells, resulting in the commitment of progenitors to become B cells. Our studies are important for understanding how EBF controls these processes in normal cells, autoimmune diseases and cancer.

描述（由申请人提供）：EBF1 是 B 淋巴细胞谱系规范和定型的关键调节因子。在缺乏 EBF1（由 Ebf1 基因编码）的小鼠中，B 细胞发育受到抑制，并且不会产生免疫球蛋白 (Ig)。最近，我们确定具有单一野生型 Ebf1 等位基因的小鼠（Ehet 小鼠）表现出骨髓 B 细胞发育缺陷。 Ehet 小鼠的 B 细胞发育进一步受损，该小鼠也拥有单一功能性 Runx1 (Rhet) 等位基因。 Runx1 编码 Runt 结构域转录因子 Runx1 (CBF12/PEBP21)，它是 EBF1 的功能伙伴。在单 Ehet 和双 (ERhet) 单倍剂量不足的小鼠中，我们观察到 1) 骨髓中 CD19+ 细胞数量大幅减少，2) 前 B 细胞标记物激活延迟，3) Ig 水平降低；轻 (L) 链重排和 4) B 细胞身份的丧失，如 B 细胞和 NK 细胞表型的混合所证明。 B 细胞身份的丧失发生在 Pax5 存在的情况下，Pax5 是 B 细胞定型的明确介体。 我们将讨论以下中心假设：EBF1 是 B 细胞谱系规范和承诺的主要调节因子。我们认为 1) EBF1 的适当剂量对于建立 B 细胞身份和进展至关重要，2) EBF1 的这种作用取决于其作为转录抑制因子的功能，这是一种未定义的机制。我们将继续研究，识别表达 EBF1 水平降低的 pro-B/pre-B 细胞中的信号传导缺陷。在最后一个目标中，我们将利用我们实验室开发的新型 Ebf1 条件敲除 (Ecko) 小鼠来解决 EBF1 是否是维持 B 细胞身份所必需的。总之，这些研究将产生关于 EBF1 在调节 B 细胞谱系规范、承诺和进展中的功能的重要新见解。 公共卫生相关性：早期 B 细胞因子 (EBF1) 对于 B 淋巴细胞的产生至关重要，B 淋巴细胞会产生针对外来病原体的抗体。在这里，我们将确定 EBF1 如何调节骨髓中这些细胞的发育。我们还将讨论 EBF 如何阻止其他类型造血细胞的基因表达，从而导致祖细胞转变为 B 细胞。我们的研究对于了解 EBF 如何控制正常细胞、自身免疫性疾病和癌症中的这些过程非常重要。