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

MYB 和 MYB-NFIB 融合在唾液腺腺样囊性癌中的作用

• 批准号: 8701485
• 负责人: CARLOS CAULIN
• 金额: $ 24万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-10 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8701485
• 关键词: Adenoid Cystic Carcinoma; Adjuvant; Adult; Animal Model; Bioinformatics; Biology; Candidate Disease Gene; Cell Line; Clinical; Code; Collaborations; Communities; Cre-LoxP; Development; Disease; Disease Progression; Distant Metastasis; Event; Exons; Experimental Models; Future; Gene Expression; Gene Fusion; Gene Targeting; Generations; Genes; Growth; High Prevalence; Human; Human Biology; Human Cell Line; Knowledge; Laboratories; Lead; Length; Low Prevalence; MYB gene; Malignant - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Molecular; Molecular Profiling; Mus; Mutation; NFIB gene; Nature; Oncogenes; Oncogenic; Operative Surgical Procedures; Outcome Study; Pathway interactions; Patients; Pre-Clinical Model; Protocols documentation; Radiation; Recurrence; Research; Resources; Role; Salivary; Salivary Glands; Survival Rate; System; Technology; Testing; Tetracyclines; Therapeutic; Transcript; Transgenic Mice; Tumor Suppressor Genes; Variant; base; cohort; design; exome sequencing; human NFIB protein; improved; in vivo; mouse model; new therapeutic target; novel; overexpression; prevent; public health relevance; response; therapy design; transgene expression; tumor; tumor progression; tumorigenic

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.

描述(申请人提供)：腺样囊性癌(ACC)是唾液腺第二常见的恶性肿瘤。超过60%的ACC患者由于生长持续缓慢、复发率高和易发生远处转移而死于该病。在过去的几十年里，在改进治疗ACC患者的治疗方法方面进展甚微，这主要是由于对ACC发生过程中涉及的基因变化的了解有限，以及缺乏针对该疾病的相关实验模型。最近在人类ACCs中发现的MYB-NFIB基因融合改变了这一前景，并刺激了新的研究途径，有望为ACC患者提供新的、更有效的治疗选择。我们与MD Anderson的Adel El-Naggar博士合作的研究发现，在大约40%的人类唾液AC中存在MYB-NFIB融合。此外，我们观察到MYB在大多数融合阳性肿瘤和超过一半的MYB基因完整的AC细胞中过表达。值得注意的是，最近对唾液AC细胞的外显子组测序证实了MYB基因的高变异率和其他癌基因或肿瘤抑制基因突变的低发生率，进一步强化了唾液AC是由MYB基因变化驱动的恶性肿瘤的概念。基于这些临床观察，在这项建议中，我们将检验假设，MYB的过度表达，作为MYB-NFIB融合的一部分或以全长形式，是ACC发生中的主要致癌事件。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，在转基因小鼠中确定MYB和MYB-NFIB的致癌潜力，其中MYB变体将仅在唾液腺中过度表达。为了最大限度地发挥这些小鼠模型的潜力，将产生一个可逆的诱导系统来诱导唾液腺中的MYB和MYB-NFIB。因此，这些小鼠将使我们能够确定抑制MYB或MYB-NFIB功能是否可以促进已建立的肿瘤的消退。这些研究将为旨在灭活MYB或MYB-NFIB融合的致癌功能以治疗ACC患者的新疗法的产生提供实验支持。在特定的目标2中，我们将确定MYB和MYB-NFIB的致癌潜力的靶基因，并将确定MYB和MYB-NFIB是否调节唾液腺中共同和/或不同的靶基因的表达。这项分析将揭示MYB调节的基因在涎腺ACC靶向治疗中的潜在应用，并将确定MYB图谱用于个性化ACC治疗的潜力。