Defining genetic pathways of plasma-cell neoplasia

描述(申请人提供)：尽管最近癌症研究取得了进展，但治疗和预防浆细胞骨髓瘤的能力仍然严重受限。浆细胞骨髓瘤是美国第二常见的血液病。解决目前的局限性将需要更多的研究努力，包括一些项目，这些项目将导致对PC恶性转化潜在的遗传途径的更好理解。这项研究计划的长期目标是改善骨髓瘤和相关PC肿瘤的预后。这项拟议的研究代表着朝着实现长期目标迈出的重要一步，其主要目标是深入了解驱动PC转型的遗传路径。我们的中心假设是，在遗传上容易发生PC恶性肿瘤的小鼠中进行无偏见的基因正向筛查将发现候选的癌症驱动基因，这些基因可以跨越鼠-人物种障碍进行评估，以便检测和验证人类PC肿瘤中的同源驱动基因。提出了三个具体的研究目标，以检验中心假设，并实现本应用的主要目标。AIMS 1和2涉及在iMyc？e转基因小鼠中识别基于逆转录病毒和转座子的癌症筛查中的候选癌症驱动基因，iMyc？e转基因小鼠是小鼠浆细胞瘤中Myc激活T(12；15)易位的基因插入模型。AIM 3致力于验证新发现的驱动基因，包括它们的人类同源基因在人类PC肿瘤中的参与。AIM 1中的研究将依赖于一种改良的莫洛尼小鼠白血病病毒MOL4070LTR。AIM 2的研究将利用双转基因睡美人(SB)体细胞突变系统，该系统使用可诱导的转座酶SB11，在PC中释放突变转座子T2/Onc2。AIM 3中的研究将首先使用生物信息学工具进行基因验证，然后利用生化、分子遗传学和生物学方法来评估选定的驱动基因作为癌症治疗和预防的新靶点的潜力。在强有力的初步结果的支持下，为这一应用提供了合理的理由，拟议的研究有望促进治疗和预防PC肿瘤的新的有针对性的方法。

DESCRIPTION (provided by applicant): Despite recent progress in cancer research, the ability to treat and prevent plasma-cell (PC) myeloma, the second most common hematologic cancer in the United States, remains severely limited. Addressing the current limitations will require additional research efforts, including projects that will lead to an enhanced understanding of the genetic pathways underlying malignant PC transformation. The long-term goal of this research program is to improve the outcome of myeloma and related PC neoplasms. The main objective of the proposed research, which represents an important step towards attaining the long-term goal, is to gain insight into the genetic pathways that drive PC transformation. Our central hypothesis is that unbiased genetic forward screening in mice that are genetically prone to PC malignancy will uncover candidate cancer driver genes that can be evaluated across the mouse-human species barrier in order to detect and validate orthologous driver genes in human PC tumors. Three specific research aims are proposed to test the central hypothesis and achieve the main objective of this application. Aims 1 and 2 are concerned with identifying candidate cancer driver genes in retrovirus- and transposon-based cancer screens in the iMyc?E¿ transgenic mouse, a gene-insertion model of the Myc-activating T(12;15) translocation in mouse plasmacytoma. Aim 3 is devoted to validating the newly discovered driver genes, including the involvement of their human orthologs in human PC tumors. The studies in Aim 1 will rely on a modified Moloney murine leukemia virus, MOL4070LTR. The studies in Aim 2 will take advantage of a double-transgenic Sleeping Beauty (SB) somatic mutagenesis system that uses the inducible transposase, SB11, to unleash the mutagenic transposon, T2/Onc2, in PCs. The studies in Aim 3 will first employ bioinformatics tools for gene validation, and then follow up with biochemical, molecular genetic and biological methods to assess the potential of selected driver genes as new targets for cancer therapy and prevention. 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 PC neoplasia.