Biological Validation of Candidate Myeloma Driver Genes

项目摘要 在我们阐明多发性骨髓瘤(MM)基因变化的能力方面取得了前所未有的进步，这导致了 正在紧急等待生物验证的候选驾驶基因清单-不仅是为了增强我们的 了解多发性骨髓瘤的自然历史和遗传基础，但也优先考虑分子靶点 用于新的骨髓瘤治疗和预防。我们将采用新开发的全面的临床前 深入评估候选骨髓瘤驱动因素的研究策略 翻译观点：叉头盒M1转录因子，FOXM1。 这项研究的长期目标是改善骨髓瘤和相关浆细胞的预后。 肿瘤。主要目的是阐明可能的骨髓瘤驱动因素，如 FOXM1，促进肿瘤的发展，获得耐药性和难治性疾病的复发。这个 中心假设是骨髓瘤驱动因素增加了肿瘤的致瘤性、克隆性和治疗抵抗力 因此，为治疗骨髓瘤的新方法提供了一个合理的分子靶点 治疗和预防。设计了三个具体的研究目标来检验这一假说，并 实现了本应用程序的目标。 AIM 1中的研究将评估FOXM1在骨髓瘤生物学和遗传学中的作用。这个 实验策略包括评估骨髓瘤细胞的药物反应，该细胞含有升高的 FOXM1及其依赖FOXM1的肿瘤进展的临床研究预期结果包括 FOXM1是有价值的新治疗方法的目标的证据，包括FDA批准的改变用途的治疗方法 毒品。AIM 2中的研究将确定FOXM1是否推动肿瘤浆细胞的发育 实验室小白鼠。实验策略依赖于确定小鼠的肿瘤发病率和发病情况。 用含有高水平FOXM1的转基因B淋巴细胞重组。还包括FOXM1- 利用荷瘤小鼠进行靶向治疗研究。预期的结果包括支持 有观点认为FOXM1促进骨髓瘤的发展，并在一定程度上决定了 骨髓瘤细胞。AIM 3中的研究将评估骨髓瘤中FOXM1的遗传网络。这个 实验策略包括确定骨髓瘤中FOXM1依赖的基因表达变化 骨髓瘤基因组中FOXM1结合部位的定位。预期结果包括 增加基于网络的对FOXM1促进肿瘤浆细胞机制的理解 发展。 有强有力的初步结果支持，这些结果为这项申请提供了充分的理由，拟议的 研究将促进治疗和预防多发性骨髓瘤的新的有针对性的方法。

Project Summary Unprecedented progress in our ability to elucidate genetic changes in multiple myeloma (MM) has led to long lists of candidate driver genes that are urgently awaiting biological validation – not only to enhance our understanding of the natural history and genetic underpinnings of MM, but also to prioritize molecular targets for new myeloma therapies and preventions. We will employ a newly developed, comprehensive preclinical research strategy to evaluate in-depth a candidate myeloma driver that appears to be very promising from a translational point of view: the forkhead box M1 transcription factor, FOXM1. The long-term goal of this research is to improve the outcome of myeloma and related plasma cell neoplasms. The main objective is to elucidate the mechanism by which putative myeloma drivers, such as FOXM1, promote tumor development, acquisition of drug resistance and relapse with refractory disease. The central hypothesis is that myeloma drivers increase the tumorigenicity, clonogenicity and therapy resistance of malignant plasma cells and, therefore, provide a rational molecular target for new approaches to myeloma treatment and prevention. Three Specific Research Aims have been designed to test this hypothesis and achieve the objective of this application. The studies in Aim 1 will evaluate the role of FOXM1 in myeloma biology and genetics. The experimental strategy includes the evaluation of drug responses in myeloma cells containing elevated levels of FOXM1 and clinical studies on FOXM1-dependent tumor progression. The anticipated outcome includes evidence that FOXM1 is a worthy target of new treatment approaches that include repurposed FDA-approved drugs. The studies in Aim 2 will determine whether FOXM1 drives neoplastic plasma cell development in laboratory mice. The experimental strategy relies on the determination of tumor incidence and onset in mice reconstituted with transgenic B-lymphocytes that harbor elevated levels of FOXM1. Also included are FOXM1- targeted treatment studies using tumor -bearing mice. The anticipated outcome includes support for the contention that FOXM1 promotes myeloma development and determines, in part, the drug response of myeloma cells. The studies in Aim 3 will assess the genetic network of FOXM1 in myeloma. The experimental strategy involves the determination of FOXM1-dependent gene expression changes in myeloma cells and the mapping of FOXM1 binding sites in the myeloma genome. The anticipated outcome includes increased network-based understanding of the mechanism by which FOXM1 promotes neoplastic plasma cell development. Supported by strong preliminary results that provide a sound rationale for this application, the proposed research is poised to facilitate novel targeted approaches to the therapy and prevention of multiple myeloma.