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

描述（由申请人提供）：Myb基因座编码c-Myb转录因子，其功能是转录激活因子和转录抑制因子。c-Myb对于最终的造血是绝对必需的，并且涉及多种造血肿瘤，包括白血病和淋巴瘤以及实体瘤。在与Calabretta及其同事的合作中，我们最近证明了单个Myb等位基因的缺失严重减少了p210BCR/ABL产生病毒转导的骨髓祖细胞中的集落形成，并延长了CML原细胞危像模型的生存期。这一发现已扩展到两种p190BCR/ Abl依赖性b细胞白血病模型中b系祖细胞的转化（Waldron等人，已提交的论文），在本提案中，我们提供了初步证据，证明c-Myb对Abl转化的前b细胞的持续存活和增殖很重要。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，由于无Myb突变的胚胎致死性，对c-Myb功能的深入了解一直很困难。我们已经产生了携带loxP靶向Myb位点的小鼠，用于Cre重组酶的条件删除。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细胞过渡到前b细胞区室以及维持前b细胞区室所必需的。此外，我们报道了c-Myb对外周B细胞稳态至关重要，缺乏c-Myb的B细胞对BAFF反应低下，表现为BAFF- r表达减少和PKC-（）的核分布增加。我们已经使用这些模型来确定在B细胞发育过程中可能介导下游c-Myb功能的c-Myb活性的暂定靶点。本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。

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.