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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：
9187891
负责人：
Robert K Bradley
金额：
$ 39.91万
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：
2015
资助国家：
美国
起止时间：
2015-12-01 至 2019-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9187891
关键词：
3&apos Splice Site Address Affect Aging Biological Models Biology Blood Cells Cell Line Cells DNA Data Development Diagnosis Disease Disease Pathway Disease remission Dysmyelopoietic Syndromes Epigenetic Process Failure Frequencies Gene Targeting Genes Genetic Goals Health Hematological Disease Hematopoiesis Hypermethylation Incidence Individual Knowledge Lead Molecular Molecular Abnormality Morbidity - disease rate Mutate Mutation Pathway interactions Patient Care Patients Phenocopy Physicians Population Protein Isoforms Proteins Proteome Public Health RNA Degradation RNA Splicing Research Ribosomal RNA Role Scientist Signal Transduction Spliced Genes Testing Therapeutic Transgenic Organisms Translating United States Work base blood group cell killing cell type effective therapy experience genome-wide improved insight killings knockout gene mortality mutant new therapeutic target novel therapeutic intervention novel therapeutics prevent public health relevance response small molecule

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. Our team consists of a basic scientist with experience in RNA splicing mechanisms and splicing- based therapeutics (Bradley) and a physician-scientist with experience in MDS biology and patient care (Shimamura). In preliminary studies, we determined how MDS-associated mutations alter U2AF1's normal role in 3' splice site recognition and identified molecular abnormalities in U2AF1-mutant cells. We propose to build on these preliminary studies with the following aims: Aim 1, Determine the mechanistic basis and consequences of the observed genetic spectrum of U2AF1 mutations; Aim 2, Determine how U2AF1 mutations dysregulate downstream molecular pathways, contributing to molecular features of dysplastic cells; Aim 3, Identify potential therapeutic opportunities for targeting U2AF1-mutant cells. The significance of these studies is that they will determine the molecular consequences of U2AF1 mutations and give insight into how spliceosomal mutations promote MDS. The health relatedness is that the proposed research may identify opportunities for selectively killing cells with U2AF1 mutations.

描述（由申请人提供）：骨髓增生异常综合征（MDS）是一组异质性血液疾病，其特征是无效和发育不良的造血。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不完全了解。最近发现的影响MDS中RNA剪接机制的高频突变为我们进一步了解MDS生物学和开发新疗法提供了重要机会。然而，剪接体突变的分子后果是未知的，阻碍了努力了解这些突变如何有助于造血发育不良，并导致新的治疗机会。为了解决这一知识差距，我们建议确定影响剪接体基因U2 AF 1（MDS中最常见的突变基因之一）的突变的机制、功能和治疗后果。我们的团队由一名在RNA剪接机制和基于剪接的治疗方面具有经验的基础科学家（布拉德利）和一名在MDS生物学和患者护理方面具有经验的医生-科学家（岛村）组成。在初步研究中，我们确定了MDS相关突变如何改变U2 AF 1在3'剪接位点识别中的正常作用，并确定了U2 AF 1突变细胞中的分子异常。我们建议在这些初步研究的基础上实现以下目标：目标1，确定观察到的U2 AF 1突变遗传谱的机制基础和后果;目标2，确定U2 AF 1突变如何失调下游分子途径，从而影响发育异常细胞的分子特征;目标3，确定针对U2 AF 1突变细胞的潜在治疗机会。这些研究的意义在于，它们将确定U2 AF 1突变的分子后果，并深入了解剪接体突变如何促进MDS。与健康相关的是，拟议的研究可能会发现选择性杀死U2 AF 1突变细胞的机会。