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U2AF1 mutations in myelodysplastic syndromes: from mechanism to therapy

骨髓增生异常综合征中的 U2AF1 突变：从机制到治疗

基本信息

批准号：
8896216
负责人：
Robert K Bradley
金额：
$ 11.44万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-04 至 2015-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8896216
关键词：
3&apos Splice Site Address Affect Aging Area Biological Biological Assay Biological Models Biology Blood Cells Cells Characteristics Chemicals Collaborations Consensus DNA Data Defect Development Diagnosis Disease Disease Pathway Disease remission Dysmyelopoietic Syndromes Dysplasia Exhibits Frequencies Genes Genomics Goals Health Hematological Disease Hematopoiesis Hematopoietic Stem Cell Transplantation Hypermethylation Incidence Individual Induced Mutation Knowledge Lead Link Measures Messenger RNA Modeling Molecular Molecular Abnormality Morbidity - disease rate Mutate Mutation Myelogenous Nucleotides Patient Care Patients Physicians Population Process Protein Isoforms Proteins Public Health RNA RNA Splicing Role Sampling Scientist Signal Transduction Site Testing Therapeutic Translating Treatment Efficacy United States Work Zinc Fingers base cell killing clinical care effective therapy experience genome-wide improved in vitro Model inhibitor/antagonist meetings molecular pathology mortality new therapeutic target novel therapeutic intervention novel therapeutics therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Myelodysplastic syndromes (MDS) are a heterogeneous group of blood disorders characterized by ineffective and dysplastic hematopoiesis. There are few effective treatments for MDS, due in part to our incomplete understanding of the molecular basis of this disease. The recent discovery of high-frequency mutations affecting the RNA splicing machinery in MDS presents a significant opportunity to further our knowledge of MDS biology and inform the development of new therapeutics. However, the molecular consequences of spliceosomal mutations ARE unknown, hindering efforts to understand how these mutations contribute to dysplastic hematopoiesis and lead to new therapeutic opportunities. To address this gap in knowledge, we propose to determine the mechanistic, functional, and therapeutic consequences of mutations affecting the spliceosomal gene U2AF1, one of the most commonly mutated genes in MDS. We have built a team with experience in RNA splicing mechanisms and splicing-based therapeutics (Bradley), as well as MDS biology and patient care (Ramakrishnan, Shimamura). In Aim 1, we will determine how MDS-associated mutations alter U2AF1's normal role in 3' splice site recognition, including causing sequence-specific alterations in U2AF1:RNA interactions. In Aim 2, we will identify mRNAs that are mis-spliced in cells with U2AF1 mutations and subsequently translated into protein, and test the hypothesis that U2AF1 mutations give rise to molecular hallmarks of MDS cells. In Aim 3, we will test the hypothesis that chemical inhibition of splice site recognition wil selectively kill cells with U2AF1 mutations. At the conclusion of this study, we will have determined the mechanistic consequences of U2AF1 mutations for the splicing process, shown how these mutations contribute to molecular pathologies characteristic of MDS cells, and tested the potential of targeting the RNA splicing process itself as a new therapeutic avenue for MDS. Ultimately, we expect the proposed work to accelerate the pace at which new therapeutics may be developed to treat MDS.

描述(申请人提供)：骨髓增生异常综合征(MDS)是一组不同类型的血液疾病，以无效和发育不良的造血为特征。MDS的有效治疗方法很少，部分原因是我们对这种疾病的分子基础了解不完全。最近在MDS中发现了影响RNA剪接机制的高频突变，这为我们进一步了解MDS生物学提供了一个重要机会，并为新疗法的开发提供了信息。然而，剪接体突变的分子后果尚不清楚，这阻碍了人们努力了解这些突变如何促进发育不良的造血并带来新的治疗机会。为了解决这一知识差距，我们建议确定影响剪接体基因U2AF1的突变的机制、功能和治疗后果，U2AF1是MDS中最常见的突变基因之一。我们已经建立了一支在RNA剪接机制和基于剪接的疗法(Bradley)以及MDS生物学和患者护理(Ramakrishnan，Shimamura)方面拥有经验的团队。在目标1中，我们将确定MDS相关突变如何改变U2AF1‘S在3’剪接位点识别中的正常角色，包括导致U2AF1：RNA相互作用中的序列特异性改变。在目标2中，我们将鉴定在U2AF1突变的细胞中错误剪接并随后翻译成蛋白质的mRNAs，并检验U2AF1突变导致MDS细胞分子特征的假设。在目标3中，我们将检验化学抑制剪接位点识别将选择性地杀死具有U2AF1突变的细胞的假设。在这项研究的结论中，我们将确定U2AF1突变对剪接过程的机制后果，展示这些突变如何促进MDS细胞的分子病理特征，并测试靶向RNA剪接过程本身作为MDS新的治疗途径的潜力。最终，我们预计拟议的工作将加快开发治疗MDS的新疗法的步伐。