Molecular Events Initiating B Cell Fate Determination

启动 B 细胞命运决定的分子事件

• 批准号: 8432053
• 负责人: Kay Lynn Medina
• 金额: $ 35.96万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-06 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8432053
• 关键词: Animal Model; Antibodies; B cell differentiation; B-Cell Development; B-Lymphocytes; Blood; Blood Cells; Bone Marrow; Cell Line; Cell Proliferation; Cell model; Commit; Data; Defect; Development; Disease; Dose; Down-Regulation; Event; Gene Expression; Gene Expression Profiling; Gene Targeting; Generations; Genes; Goals; Health; Hematological Disease; Hematopoietic; Hematopoietic stem cells; Homeostasis; HoxA protein; Immune system; Immunodeficiency and Cancer; Immunologic Deficiency Syndromes; Infection; Intervention; Knowledge; Learning; Leukocytes; Life; Ligands; Link; Lymphoid; Lymphopoiesis; Mediating; Microarray Analysis; Molecular; Molecular Target; Mus; Pathway interactions; Pattern; Play; Process; Production; Proteins; Rag1 Mouse; Receptor Protein-Tyrosine Kinases; Regulation; Regulator Genes; Reporter; Research Design; Role; Series; Signal Transduction; Stem Cell Development; Stem cells; TCF3 gene; Testing; Transcript; animal data; base; cytokine; design; fighting; functional genomics; helix-loop-helix protein differentiation inhibitor; humoral immunity deficiency; insight; interest; leukemia; novel; overexpression; progenitor; protein B; research study; stem cell biology; transcription factor

DESCRIPTION (provided by applicant): B lymphocytes are critical blood cells and altered production or function can cause significant disease. We are interested in understanding how blood stem cells initiate B cell development. Delineating the normal B cell developmental pathway will provide insight into the molecular and cellular basis of many hematologic diseases. Although considerable progress has been made in understanding the generation of naive B cells from committed B cell precursors, little is known about how this process begins. This project will exploit exciting new findings concerning an unexpected regulatory connection between the receptor tyrosine kinase Flt3, HoxA proteins, and the B cell fate determinant EBF. Our new data suggest that this regulatory connection plays an important role in regulating the stem cell to Pro-B transition, and hence, the numbers of B lymphocytes generated. Specifically, we will learn how Flt3 signaling initiates a series of events, gradually biasing multipotential progenitors in bone marrow into the B lineage. Exciting new data revealed that Flt3 signaling, in a ligand-dose dependent fashion, regulates the activity of the primary B cell fate determinant, E2A, a key regulator of the EBF gene. Once expressed, EBF orchestrates B cell differentiation. Gene expression profiling of an EBF-/- cell line pointed to novel role for EBF during B cell development, namely controlling expression of a developmentally regulated cluster of HoxA proteins. Elucidating regulatory circuits that control HoxA expression is important, as dysregulated expression impairs B cell differentiation. First we will determine the molecular events between Flt3 signaling and EBF expression. Then we will determine the regulatory connection between EBF, HoxA, and Flt3 that controls the production of B lymphocytes. Overall, these experiments will provide basic knowledge of a vital process, the production of white blood cells that make antibodies to fight infections. The information should help identify molecular targets for intervention in blood cell cancers and immunodeficiency diseases.

描述（由申请人提供）：B淋巴细胞是关键的血细胞，产生或功能的改变会导致重大疾病。我们有兴趣了解血液干细胞如何启动B细胞的发育。描述正常B细胞​​发育途径将为许多血液学疾病的分子和细胞基础提供洞察力。尽管在理解固定的B细胞前体的幼稚B细胞的产生方面取得了很大进展，但对该过程的开始知之甚少。该项目将利用有关受体酪氨酸激酶FLT3，HOXA蛋白和B细胞命运决定因素EBF之间意外调节连接的令人兴奋的新发现。我们的新数据表明，这种调节性连接在调节干细胞对pro-b转变以及产生的B淋巴细胞数量中起着重要作用。具体而言，我们将学习FLT3信号如何启动一系列事件，逐渐使骨髓中的多次祖细胞偏向B谱系。令人兴奋的新数据表明，FLT3信号以配体依赖性方式调节了EBF基因的关键调节剂E2A的主要B细胞命运决定簇的活性。一旦表达，EBF就会策划B细胞分化。 EBF - / - 细胞系的基因表达分析指向B细胞发育过程中EBF的新作用，即控制发育调节的HOXA蛋白簇的表达。阐明控制HOXA表达的调节回路很重要，因为失调的表达会损害B细胞分化。首先，我们将确定FLT3信号传导和EBF表达之间的分子事件。然后，我们将确定控制B淋巴细胞产生的EBF，HOXA和FLT3之间的调节连接。总体而言，这些实验将提供有关至关重要过程的基本知识，即产生抗体感染的抗体的白细胞的产生。该信息应有助于确定用于干预血细胞癌和免疫缺陷疾病的分子靶标。

项目成果

Hoxa9 regulates Flt3 in lymphohematopoietic progenitors.

• DOI: 10.4049/jimmunol.0904203
• 发表时间: 2010-12-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Gwin K;Frank E;Bossou A;Medina KL
• 通讯作者: Medina KL

Cell extrinsic alterations in splenic B cell maturation in Flt3-ligand knockout mice.

• DOI: 10.1002/iid3.54
• 发表时间: 2015-06
• 期刊: IMMUNITY INFLAMMATION AND DISEASE
• 影响因子: 3.2
• 作者: Dolence, Joseph J;Gwin, Kimberly A;Shapiro, Mariya B;Hsu, Fan-Chi;Shapiro, Virginia S;Medina, Kay L
• 通讯作者: Medina, Kay L

Developmental stage-specific effects of Pim-1 dysregulation on murine bone marrow B cell development.

• DOI: 10.1186/s12865-016-0152-1
• 发表时间: 2016-06-10
• 期刊: BMC immunology
• 影响因子: 3
• 作者: Xu Z;Gwin KA;Li Y;Medina KL
• 通讯作者: Medina KL

Differential requirement for Hoxa9 in the development and differentiation of B, NK, and DC-lineage cells from Flt3+ multipotential progenitors.

来自 Flt3 多能祖细胞的 B、NK 和 DC 谱系细胞的发育和分化对 Hoxa9 的差异要求。

• DOI: 10.1186/1471-2172-14-5
• 发表时间: 2013
• 期刊: BMC immunology
• 影响因子: 3
• 作者: Gwin,Kimberly;Dolence,JosephJ;Shapiro,MariyaB;Medina,KayL
• 通讯作者: Medina,KayL

Separation of plasmacytoid dendritic cells from B-cell-biased lymphoid progenitor (BLP) and Pre-pro B cells using PDCA-1.

• DOI: 10.1371/journal.pone.0078408
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Medina KL;Tangen SN;Seaburg LM;Thapa P;Gwin KA;Shapiro VS
• 通讯作者: Shapiro VS