c-Myb fusion proteins in Adenoid Cystic Carcinoma

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。在最近的一项合作工作中，我们最近证明了单个Myb等位基因的丢失严重减少了用产生p210BCR/ABL的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。这一发现已经扩展到两种依赖p190BCR/ABL的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与小鼠和禽类肿瘤有关，但直到最近有报道称，在几种人类癌症中涉及MYB基因的染色体易位和微妙的基因扩增，才有相对较少的直接证据表明c-Myb与人类癌症有关。因此，了解c-Myb在人类肿瘤中的功能并确定c-Myb活性的下游介质对于理解c-Myb功能在人类癌症中的相关性至关重要。Stenman和他的同事最近在腺样囊性癌(ACC)中发现了一种复发的肿瘤特异性t(6；9)(q22-23；p23-24)染色体易位，涉及MYB和NFIB基因座。这种易位在ACC中的反复和独特的表现表明，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基础作用。我们提出了两个目的来测试由此产生的c-Myb/NFIB蛋白对ACC的意义。如果c-Myb/NFIB融合蛋白(S)被证明在ACC的维持或启动过程中起重要作用，本研究中建立的试剂将为了解ACC的生物学特性提供宝贵的资源，识别c-Myb/NFIB融合蛋白在ACC中的下游中介基因，并可能提供治疗靶点。 公共卫生相关性：Myb基因座编码c-Myb原癌基因，其功能是转录调节。C-Myb是正常造血所必需的，与多种人类白血病、淋巴瘤和其他恶性肿瘤(如乳腺癌和结肠癌)有关，但人们对c-Myb在人类癌症中的作用知之甚少。这项建议中概述的实验将确定最近在腺样囊性癌(ACC)中发现的一致染色体易位产生的融合蛋白是否对ACC的启动和维持至关重要。拟议工作的完成将阐明c-Myb/NFIB融合蛋白在ACC中所起的作用，并开始确定在ACC中充当下游介体的关键c-Myb/NFIB靶标。这些靶点可能被证明是潜在的治疗靶点。

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. PUBLIC HEALTH RELEVANCE: The Myb locus encodes the c-Myb proto-oncogene, which functions as a transcription regulator. c-Myb is absolutely required for normal hematopoiesis and is associated with a wide variety of human leukemias, lymphomas and other malignancies such as breast and colon cancer yet little is understood about c-Myb function in human cancer. The experiments outlined in this proposal will determine if the fusion protein resultant from a recently identified consistent chromosomal translocation in Adenoid Cystic Carcinoma (ACC) that produces a c-Myb/NFIB fusion protein is important for initiation and maintenance of ACC. Completion of the proposed work will clarify the role played by c-Myb/NFIB fusion proteins in ACC and begin to identify crucial c-Myb/NFIB targets that serve as downstream mediators in ACC. These targets may prove to be potential therapeutic targets.