Molecular Pathogenesis of MLL-Fusion Gene Leukemia

MLL融合基因白血病的分子发病机制

• 批准号: 7259619
• 负责人: Ashish Kumar
• 金额: $ 14万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-25 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7259619
• 关键词: Address; Advanced Development; Biology; Bone Marrow Cells; Candidate Disease Gene; Cell Line; Cell Transplants; Cells; Chimeric Proteins; Cloning; DNA Sequence Rearrangement; Data; Development; Disease; Environment; Equilibrium; Event; Experimental Models; Fostering; Future; Gene Expression; Gene Expression Regulation; Gene Targeting; Generations; Genes; Genome; Goals; Growth; Hematopoietic; Human; Infant; Knock-in Mouse; Knowledge; Lead; Lymphoid; MLL gene; Malignant Neoplasms; Maps; Mediating; Mediator of activation protein; Mentors; Minnesota; Molecular; Molecular Profiling; Murine leukemia virus; Mus; Mutate; Mutation; Myeloid Leukemia; Myeloproliferative disease; Outcome; Pathogenesis; Pathway interactions; Personal Satisfaction; Physiology; Population; Process; Proto-Oncogenes; Publishing; RNA Interference; Research; Research Personnel; Research Project Grants; Resistance; Site; Stem cells; Study models; Testing; Time; Transgenic Organisms; Tumor Suppressor Genes; Universities; Virus; Wild Type Mouse; alpha-Thalassemia; base; experience; fusion gene; innovation; insight; leukemia; leukemic stem cell; mouse model; novel; progenitor; programs; self-renewal

DESCRIPTION (provided by applicant): Project Summary: Majority of infant leukemias involve rearrangements in the MLL gene and are most often fatal. There is a fundamental gap in our understanding of how MLL rearrangements cause leukemia. The long term goal is to advance the development of targeted therapies for MLL-fusion gene leukemia. The objective of this application is to identify the molecular pathways that mediate the pathogenesis of MLL-fusion gene leukemia. The experimental model studied will be knock-in mice carrying the MLL-AF4 or MLL-AF9 fusion gene. The first specific aim is to identify the downstream target genes of MLL-AF4 and MLL-AF9 that induce growth deregulation. The central hypothesis is that the key targets of the fusion proteins are the genes differentially expressed in the hematopoietic sub-population that displays the greatest growth deregulation. The experimental strategy will be comparison of gene expression profiles of purified hematopoietic progenitor/ stem cells from MLL-AF4, MLL-AF9 and wild type mice. Functional significance of the candidate genes will be tested using RNA interference in leukemia cell lines. The second specific aim is to identify mutations that co-operate with the MLL-fusion genes in the pathogenesis of leukemia. The knock-in mice display expansion of hematopoietic progenitors prenatally, yet leukemia development takes several months. The central hypothesis is that co-operating mutations will accelerate development of leukemia. Young mice will be infected with murine leukemia viruses that integrate into the genome and either activate or inactivate neighboring genes. Cloning and sequencing of integration sites will identify cooperating mutations. The cooperative actions of candidate genes will be tested by expressing them in knock-in bone marrow cells and transplanting these cells into recipient mice. The proposed studies are innovative since they address gene regulation by MLL-fusion proteins in a cell-specific context and will provide data on accessory mutational events in MLL-fusion gene leukemia. The proposed research is significant because it will enhance the understanding of the pathogenesis of MLL-rearranged leukemias. Relevance: Effective therapies for MLL-leukemias are limited by the lack of knowledge of the underlying biology of the disease process. The results of the proposed research will help the development of effective therapies for this dreadful disease.

描述（由申请人提供）：项目摘要：大多数婴儿白血病涉及MLL基因中的重排，并且通常是致命的。我们对MLL重排如何引起白血病的理解存在根本的差距。长期目标是提高针对MLL融合基因白血病的靶向疗法的发展。该应用的目的是确定介导MLL融合基因白血病发病机理的分子途径。研究的实验模型将是带有MLL-AF4或MLL-AF9融合基因的敲入小鼠。第一个具体目的是确定诱导生长放松管制的MLL-AF4和MLL-AF9的下游靶基因。中心假设是，融合蛋白的关键靶标是在造血亚群中差异表达的基因，该基因显示出最大的生长失调。实验策略将是比较来自MLL-AF4，MLL-AF9和野生型小鼠的纯化造血祖细胞/干细胞的基因表达谱。候选基因的功能意义将使用白血病细胞系中的RNA干扰进行测试。第二个具体目的是鉴定白血病发病机理中与MLL融合基因合作的突变。敲入小鼠在产前表现出造血祖细胞的扩张，但白血病发育需要几个月的时间。中心假设是合作突变将加速白血病的发展。年轻小鼠将被鼠白血病病毒感染，这些病毒将整合到基因组中并激活或失活的基因。集成位点的克隆和测序将确定合作的突变。候选基因的合作作用将通过在敲打骨髓细胞中表达并将这些细胞移植到受体小鼠中来测试。拟议的研究具有创新性，因为它们在细胞特异性环境中通过MLL融合蛋白来调节基因调节，并将提供有关MLL融合基因白血病中辅助突变事件的数据。拟议的研究很重要，因为它将增强对MLL重新延长白血病的发病机理的理解。相关性：MLL- leukemias的有效疗法受到对疾病过程的潜在生物学知识的了解的限制。拟议的研究结果将有助于开发这种可怕疾病的有效疗法。