Regulation of B Cell Identity and Lineage Progression

B 细胞身份和谱系进展的调节

• 批准号: 8420487
• 负责人: James R. Hagman
• 金额: $ 36.29万
• 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/8420487
• 关键词: Address; Alleles; Antibodies; Autoimmune Diseases; B-Cell Development; B-Lymphocytes; Bone Marrow; CD19 gene; Cell Lineage; Cells; Core-Binding Factor; DNA Sequence Rearrangement; Defect; Development; Exhibits; Gene Expression; Gene Rearrangement; Gene Targeting; Genes; Genetic Transcription; Hematopoietic; Immunoglobulin Genes; Immunoglobulins; Knockout Mice; Laboratories; Light; Light-Chain Immunoglobulins; 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.

描述（由申请人提供）：EBF1是B淋巴细胞谱系规范和承诺的关键调节因子。在缺乏EBF1（由EBF1基因编码）的小鼠中，B细胞发育受阻，免疫球蛋白（Ig）不产生。最近，我们确定具有单一野生型Ebf1等位基因的小鼠（Ehet小鼠）在骨髓中表现出B细胞发育缺陷。在具有单一功能Runx1 （Rhet）等位基因的Ehet小鼠中，B细胞发育进一步受损。Runx1编码Runt结构域转录因子Runx1 (CBF12/PEBP21)，这是EBF1的功能伙伴。在单eheet和双（erheet）单倍体不足的小鼠中，我们观察到1)骨髓中CD19+细胞数量显著减少，2)前b细胞标记物的激活延迟，3)Ig水平降低；轻(L)链重排和4)B细胞身份的丧失，B细胞和NK细胞表型的混合证明了这一点。B细胞身份的丧失发生在Pax5存在的情况下，Pax5是一种确定的B细胞承诺的中介。我们将讨论EBF1是B细胞谱系规范和承诺的主要调节因子的中心假设。我们提出，1)适当剂量的EBF1对B细胞的身份和进展至关重要，2)EBF1的作用依赖于其作为转录抑制因子的功能，其机制尚不明确。我们将继续我们的研究，以确定表达EBF1水平降低的pro-B/pre-B细胞中的信号缺陷。在最后一个目标中，我们将利用我们实验室开发的新的EBF1条件敲除（Ecko）小鼠来解决EBF1是否需要维持B细胞的身份。总之，这些研究将对EBF1在B细胞谱系规范、承诺和进展的调节中的功能产生重要的新见解。