c-Myb fusion proteins in Adenoid Cystic Carcinoma

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。在一项合作努力中，我们最近证明了单个Myb等位基因的丢失严重降低了用产生p210 BCR/ABL的病毒转导的骨髓祖细胞的集落形成，并延长了CML急变模型中的存活期。这一发现已扩展到两种p190 BCR/ABL依赖性B细胞白血病模型中B系祖细胞的转化。尽管有明确的证据表明c-Myb参与小鼠和禽类肿瘤，但相对较少的直接证据表明c-Myb参与人类癌症，直到最近报道了几种人类癌症中涉及MYB基因座的染色体易位和微妙的基因扩增。因此，了解c-Myb在人类肿瘤中的功能并鉴定c-Myb活性的下游介质对于了解c-Myb功能在人类癌症中的相关性至关重要。Stenman及其同事最近发现了一种复发性和肿瘤特异性t（6;9）（q22-23;p23-24）染色体易位，涉及腺样囊性癌（ACC）中的MYB和NFIB基因座。这种易位在ACC中的反复出现和独特的表现表明易位事件和由此产生的c-Myb/NFIB融合蛋白可能在这些肿瘤中发挥重要作用。我们提出了两个目的来测试所得的c-Myb/NFIB蛋白对ACC的意义。如果c-Myb/NFIB融合蛋白被证明对于ACC的维持或起始是重要的，则在该提议中产生的试剂将提供有价值的资源来理解ACC的生物学，鉴定作为ACC中c-Myb/NFIB融合蛋白的下游介体的靶基因，并且可以提供治疗靶点。

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 hematopoietic tumors including leukemia and lymphoma as well as solid tumors. In a collaborative effort, 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. Despite clear evidence for the involvement of c-Myb in mouse and avian tumors relatively little direct evidence has implicated c-Myb in human cancer until recent reports of chromosomal translocations and subtle gene amplification involving the MYB locus in several human cancers. Thus, understanding c-Myb function in human tumors and identifying the downstream mediators of c-Myb activity is crucial for understanding the relevance of c-Myb function in human cancer. Stenman and colleagues have recently identified a recurrent and tumor specific t(6;9)(q22-23;p23-24) chromosomal translocation that involves the MYB and NFIB loci in adenoid cystic carcinoma (ACC). The recurrent and unique representation of this translocation in ACC suggests that the translocation event and the resulting c-Myb/NFIB fusion protein may play a fundamental role in these tumors. We propose two aims to test the significance of the resulting c- Myb/NFIB proteins to ACC. If c-Myb/NFIB fusion protein(s) proves to be important for the maintenance or initiation of ACC, the reagents generated in this proposal will provide valuable resources to understand the biology of ACC, identify target genes that are downstream mediators of the c-Myb/NFIB fusion protein in ACC and may provide therapeutic targets.