Role of MYB and MYB-NFIB fusions in Salivary Adenoid Cystic Carcinoma

描述（由申请人提供）：腺样囊性癌（ACC）是第二常见的唾液腺恶性肿瘤。由于ACC持续生长缓慢，复发率高，易发生远处转移，超过60%的ACC患者死于该病。在过去的几十年中，在改善治疗ACC患者的疗法方面几乎没有取得进展，主要是由于对ACC发展中涉及的遗传改变的知识有限以及缺乏该疾病的相关实验模型。最近在人类ACC中发现MYB-NFIB基因融合改变了这一前景，并刺激了新的研究途径，预计将为ACC患者带来新的和更有效的治疗选择。我们与MD安德森的阿德尔El-Naggar博士的合作研究在约40%的人唾液ACC中鉴定了MYB-NFIB融合体。此外，我们在大多数融合阳性肿瘤和超过一半的MYB基因完整的ACC中观察到MYB过表达。值得注意的是，最近唾液ACC的外显子组测序证实了MYB改变的高发生率和其他癌基因或肿瘤抑制基因突变的低发生率，进一步加强了唾液ACC是由MYB基因改变驱动的恶性肿瘤的观点。基于这些临床观察，在本研究中，我们将检验MYB过表达作为MYB-NFIB融合的一部分或全长形式是ACC发展中的主要致癌事件的假设。为了验证这一假设，在特定目标1中，我们将使用我们实验室优化的诱导系统，确定MYB和MYB-NFIB在转基因小鼠中的致癌潜力，其中MYB变体将仅在唾液腺中过表达。为了最大化这些小鼠模型的潜力，将产生可逆诱导系统以诱导唾液腺中的MYB和MYB-NFIB。因此，这些小鼠将使我们能够确定MYB或MYB-NFIB功能的抑制是否可以促进已建立的肿瘤的消退。这些研究将提供实验支持的新疗法，旨在验证MYB或MYB-NFIB融合的致癌功能，以治疗ACC. In具体目标2患者，我们将确定MYB和MYB-NFIB的靶基因，有助于其致癌潜力，并将确定是否MYB和MYB-NFIB调节共同和/或不同的靶基因在唾液腺的表达。这项分析将揭示MYB调控的基因与唾液腺ACC的靶向治疗的潜在应用，并将确定MYB分析的潜力，以个性化ACC治疗。

DESCRIPTION (provided by applicant): Adenoid cystic carcinoma (ACC) is the second most common malignancy of the salivary glands. Over 60% of the ACC patients succumb to the disease as a result of the persistent slow growth, high recurrence rates and propensity to distant metastasis. During the past decades little progress has been made in improving therapies to treat ACC patients, primarily due to the limited knowledge of the genetic alterations involved in ACC development and the lack of relevant experimental models for the disease. The recent discovery of the MYB- NFIB gene fusion in human ACCs has changed this outlook and stimulated new avenues of research that are expected to lead to novel and more effective therapeutic options for ACC patients. Our collaborative studies with Dr. Adel El-Naggar in MD Anderson, identified MYB-NFIB fusions in approximately 40% of the human salivary ACCs. In addition, we observed MYB overexpression in most of the fusion-positive tumors and over half of the ACCs in which the MYB gene was intact. Notably, recent exome sequencing of salivary ACCs confirmed the high rates of MYB alterations and the low prevalence of mutations in other oncogenes or tumor suppressor genes, further reinforcing the notion that salivary ACC is a malignancy driven by alterations in the MYB gene. Based on these clinical observations, in this proposal we will test the hypothesis that MYB overexpression, as part of the MYB-NFIB fusion or in the full-length form, is a primary oncogenic event in ACC development. To test this hypothesis, in Specific Aim 1 we will determine the oncogenic potential of MYB and MYB-NFIB in transgenic mice in which the MYB variants will be overexpressed exclusively in the salivary glands, using an inducible system optimized in our laboratory. To maximize the potential of these mouse models, a reversible inducible system will be generated to induce MYB and MYB-NFIB in salivary glands. Thus, these mice will allow us to determine whether suppression of the MYB or MYB-NFIB functions can promote regression of established tumors. These studies will provide the experimental support for the generation of new therapies designed to inactivate the oncogenic function of MYB or MYB-NFIB fusions to treat patients with ACC. In Specific Aim 2 we will identify MYB and MYB-NFIB target genes that contribute to their oncogenic potential and will determine whether MYB and MYB-NFIB regulate the expression of common and/or distinct targets genes in salivary glands. This analysis will uncover MYB-regulated genes with potential applications to targeted therapy for salivary ACC and will determine the potential of MYB profiling to personalize ACC treatment.