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

描述(申请人提供)：Myb基因座编码c-Myb转录因子，它既是转录激活因子，也是转录抑制因子。C-Myb对于最终的造血是绝对必要的，并且已经与包括白血病、淋巴瘤以及实体瘤在内的多种造血肿瘤有关。最近，我们与Calabretta及其同事合作，证明了单个Myb等位基因的丢失严重减少了p210BCR/ABL产生病毒转导的骨髓祖细胞的克隆形成，并延长了CML原始细胞危机模型中的存活时间。这一发现已经扩展到两个p190BCR/ABL依赖的B细胞白血病模型中B系祖细胞的转化(Waldron等人，提交了手稿)，在这个建议中，我们提供了初步的证据，表明c-Myb对于Abl转化的前B细胞的持续生存和增殖是重要的。因此，了解c-Myb在正常造血过程中的作用并确定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在癌症中的作用是至关重要的。然而，由于Myb零突变对胚胎的致命性，深入了解c-Myb的功能一直是困难的。我们已经产生了携带loxP靶向Myb基因座的小鼠，通过Cre重组酶有条件地删除。我们用这些小鼠来确定B细胞发育过程中需要c-Myb的临界点。C-Myb对于前B细胞的发育、增殖和存活、从前B细胞向前B细胞的转变以及前B细胞的维持都是必需的。此外，我们还报道了c-Myb对外周B细胞动态平衡的关键作用，c-Myb缺陷的B细胞对BAFF反应低下，表现为BAFF-R表达减少和PKC-()核分布增加。我们使用这些模型来确定c-Myb活性的试探性靶点，这些靶点可能在B细胞发育过程中介导c-Myb下游功能。这项提议的目标是开发在B细胞发育的不同阶段调节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.