Defining genetic pathways of plasma-cell neoplasia

定义浆细胞肿瘤的遗传途径

• 批准号: 8113449
• 负责人: Siegfried Janz
• 金额: $ 30.39万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-19 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8113449
• 关键词: Address; Applications Grants; Basic Science; Biochemical; Bioinformatics; Biological; Cataloging; Catalogs; Cells; Cessation of life; Complement; Event; Genes; Genetic; Genetic Screening; Genomics; Germinal Center B-Lymphocyte; Goals; Hematologic Neoplasms; Human; Lead; Malignant - descriptor; Malignant Neoplasms; Maps; Methods; Mission; Modeling; Molecular Genetics; Moloney Leukemia Virus; Multiple Myeloma; Mus; Mutagenesis; Neoplasms; Neoplastic Plasma Cell; Orthologous Gene; Outcome; Pathway interactions; Pattern; Phase; Phenotype; Plasma Cell Neoplasm; Plasma Cells; Plasmacytoma; Prevention; Prevention therapy; Preventive; Public Health; Research; Research Project Grants; Retroviridae; Role; Screening for cancer; Screening procedure; Site; Sleeping Beauty; Staging; System; Testing; TimeLine; Transgenes; Transgenic Mice; Transgenic Organisms; Translating; Transposase; United States; Validation; Virus; Work; activation-induced cytidine deaminase; anticancer research; base; cancer genetics; cancer prevention; cancer therapy; cell transformation; flexibility; follow-up; gene discovery; improved; innovation; insight; mouse model; new therapeutic target; novel; plasma cell development; prevent; programs; public health relevance; sound; tool; tumor; tumor progression

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.

描述（由申请人提供）：尽管最近癌症研究取得了进展，但治疗和预防浆细胞（PC）骨髓瘤（美国第二大常见血液学癌症）的能力仍然严重有限。解决目前的限制将需要额外的研究努力，包括将导致加深理解恶性PC转化的遗传途径的项目。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。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，在遗传上倾向于PC恶性肿瘤的小鼠中进行无偏倚的遗传正向筛选，将发现候选的癌症驱动基因，这些基因可以跨越小鼠-人类物种屏障进行评估，以检测和验证人类PC肿瘤的同源驱动基因。提出了三个具体的研究目标，以检验中心假设，实现本应用的主要目标。目的1和2涉及在iMyc中基于逆转录病毒和转座子的癌症筛查中识别候选癌症驱动基因。转基因小鼠，myc激活T（12;15）易位小鼠浆细胞瘤的基因插入模型。Aim 3致力于验证新发现的驱动基因，包括它们在人类PC肿瘤中的人类同源物。Aim 1的研究将依赖于一种改良的Moloney小鼠白血病病毒MOL4070LTR。Aim 2的研究将利用双转基因睡美人（SB）体细胞诱变系统，该系统使用可诱导转座酶SB11释放pc中的诱变转座子T2/Onc2。Aim 3的研究将首先使用生物信息学工具进行基因验证，然后使用生化，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新靶点的潜力。在强有力的初步结果的支持下，为该应用提供了合理的理论基础，该研究有望促进新的靶向治疗和预防PC瘤变的方法。