Defining genetic pathways of plasma-cell neoplasia

描述（由申请人提供）：尽管癌症研究取得了最新进展，但治疗和预防浆细胞（PC）骨髓瘤（美国第二大常见血液癌症）的能力仍然非常有限。解决目前的局限性将需要更多的研究工作，包括项目，将导致进一步了解的遗传途径的恶性PC转化。该研究项目的长期目标是改善骨髓瘤和相关PC肿瘤的结局。拟议研究的主要目标是深入了解驱动PC转化的遗传途径，这是实现长期目标的重要一步。我们的中心假设是，在遗传上易患PC恶性肿瘤的小鼠中进行无偏遗传前向筛选将发现候选癌症驱动基因，这些基因可以通过小鼠-人类物种屏障进行评估，以检测和验证人类PC肿瘤中的正向驱动基因。提出了三个具体的研究目标，以检验中心假设，实现本申请的主要目标。目的1和2是与确定候选人的癌症驱动基因在逆转录病毒和转座子为基础的癌症屏幕中的iMyc？转基因小鼠，一种Myc激活T（12;15）易位的基因插入模型。目标3致力于验证新发现的驱动基因，包括其人类直系同源物在人类PC肿瘤中的参与。目标1中的研究将依赖于改良的莫洛尼鼠白血病病毒MOL 4070 LTR。目标2中的研究将利用双转基因睡美人（SB）体细胞诱变系统，该系统使用诱导型转座酶SB 11在PC中释放诱变转座子T2/Onc 2。目标3的研究将首先采用生物信息学工具进行基因验证，然后采用生物化学、分子遗传学和生物学方法评估选定的驱动基因作为癌症治疗和预防新靶点的潜力。在强有力的初步结果的支持下，为这一应用提供了合理的依据，拟议的研究有望促进新的靶向方法来治疗和预防PC肿瘤。 公共卫生相关性：浆细胞骨髓瘤，通常称为多发性骨髓瘤，是世界范围内最常见和最致命的浆细胞肿瘤，也是第二常见的血液恶性肿瘤。本文提出的研究将利用Myc转基因小鼠模型中的两个互补的，无偏见的遗传正向筛选来增强我们对恶性浆细胞转化的遗传途径的理解，并激发新的靶向方法来治疗和预防人类浆细胞肿瘤。

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. PUBLIC HEALTH RELEVANCE: Plasma-cell myeloma, commonly known as multiple myeloma, is the most prevalent and fatal plasma-cell neoplasia and the second-most common hematologic malignancy worldwide. The research proposed here will take advantage of two complementary, unbiased, genetic-forward screenings in a Myc-transgenic mouse model of human plasma-cell neoplasia to enhance our understanding of the genetic pathways underlying malignant plasma-cell transformation and inspire new targeted approaches to the treatment and prevention of human plasma-cell neoplasms.