c-Myb controls survival, proliferation and differentiation during B-lymphopoiesis

c-Myb 控制 B 淋巴细胞生成过程中的存活、增殖和分化

• 批准号: 8325520
• 负责人: Timothy P. Bender
• 金额: $ 28.84万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8325520
• 关键词: Alleles; B-Cell Development; B-Lymphocytes; Blast Cell; Blast Phase; Bone Marrow; CD19 gene; Candidate Disease Gene; Chronic Lymphocytic Leukemia; Collaborations; Colon Carcinoma; Data; Development; Embryo; Genes; Genetic Transcription; Goals; Hematopoiesis; Homeostasis; Human; Lymphopoiesis; MYB gene; Maintenance; Malignant Neoplasms; Manuscripts; Mediating; Mediator of activation protein; Modeling; Mus; Mutation; Nuclear; Peripheral; Play; Process; Proto-Oncogene Proteins c-myb; Proto-Oncogenes; Publishing; Reporting; Role; Solid; Solid Neoplasm; Staging; Transcription Coactivator; Transcription Repressor/Corepressor; Virus; Work; abl Oncogene; base; insight; leukemia/lymphoma; malignant breast neoplasm; progenitor; recombinase; therapeutic target; transcription factor; tumor

DESCRIPTION (provided by applicant): The Myb locus encodes the c-Myb transcription factor, which functions as both a transcription activator and repressor. c-Myb is absolutely required for definitive hematopoiesis and has been implicated in a variety of hematopoitic tumors including leukemia and lymphoma as well as solid tumors. In collaboration with Calabretta and colleagues, we recently demonstrated that loss of a single Myb allele severely reduces colony formation in bone marrow progenitors transduced with a p210BCR/ABL producing virus and extended survival in a model of CML blast crisis. This finding has been extended to transformation of B-lineage progenitors in two models of p190BCR/ABL-dependent B-cell leukemia (Waldron et al., manuscript submitted) and in this proposal we provide preliminary evidence that c-Myb is important for the continued survival and proliferation of Abl transformed pre-B cells. Thus, understanding what c-Myb does during normal hematopoiesis and identifying the downstream mediators of c-Myb activity is crucial for understanding c-Myb function during normal hematopoiesis and how c-Myb may function in cancer. However, gaining insight into c-Myb function has been difficult due to the embryonic lethality of null Myb mutations. We have produced mice that carry a loxP targeted Myb locus for conditional deletion by Cre recombinase. We have used these mice to define critical points during B cell development where c-Myb is required. c-Myb is required for the development, proliferation and survival of pro-B cells, transition from the pro-B to pre-B cell compartment as well as maintenance of the pre-B cell compartment. In addition, we reported that c-Myb is crucial for peripheral B cell homeostasis and that c-Myb deficient B cells are hyporesponsive to BAFF, displaying both reduced expression of BAFF-R and increased nuclear distribution of PKC-(. We have used these models to identify tentative targets of c-Myb activity that may mediate downstream c-Myb functions during B cell development. The goal of this proposal is to develop the network of crucial genes that mediate c-Myb activity during different stages of B cell development.

描述（由申请人提供）：Myb基因座编码c-Myb转录因子，其同时作为转录激活因子和阻遏因子发挥作用。c-Myb是确定性造血作用所绝对需要的，并且已经涉及多种造血肿瘤，包括白血病和淋巴瘤以及实体瘤。最近，我们与Calcoletta及其同事合作，证明了单个Myb等位基因的丢失严重减少了用产生p210 BCR/ABL的病毒转导的骨髓祖细胞的集落形成，并延长了CML急变模型的存活期。这一发现已经扩展到两种p190 BCR/ABL依赖性B细胞白血病模型中B系祖细胞的转化（沃尔德龙等人，在该提案中，我们提供了c-Myb对于Abl转化的前B细胞的持续存活和增殖是重要的初步证据。因此，了解c-Myb在正常造血过程中的作用以及确定c-Myb活性的下游介质对于了解c-Myb在正常造血过程中的功能以及c-Myb如何在癌症中发挥作用至关重要。然而，由于Myb无效突变的胚胎致死性，深入了解c-Myb功能一直很困难。我们已经产生了携带IoxP靶向Myb基因座的小鼠，用于通过Cre重组酶进行条件性缺失。我们使用这些小鼠来确定B细胞发育过程中需要c-MyB的临界点。c-Myb是前B细胞的发育、增殖和存活、从前B细胞区室向前B细胞区室的转变以及前B细胞区室的维持所必需的。此外，我们还报道了c-Myb对外周B细胞的稳态至关重要，并且c-Myb缺陷的B细胞对BAFF反应低下，表现出BAFF-R表达降低和PKC-（？）我们已经使用这些模型来确定c-MyB活性的暂定靶标，其可能在B细胞发育期间介导下游c-MyB功能。该提案的目标是开发在B细胞发育的不同阶段介导c-MyB活性的关键基因网络。