Genetic and molecular basis for SRSF2 mutations in myelodysplasia

骨髓增生异常中 SRSF2 突变的遗传和分子基础

• 批准号: 10241323
• 负责人: Omar Abdel-Wahab
• 金额: $ 51.96万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10241323
• 关键词: Acute Myelocytic Leukemia; Affect; Affinity; Alleles; Alternative Splicing; Antisense Oligonucleotides; Automobile Driving; Binding; Biological; Biological Response Modifier Therapy; Blood; Blood Cells; Bone Marrow; Catalysis; Cell Survival; Cells; Clinical Research; Clinical Trials; Collaborations; Complement; Consensus; Disease; Dysmyelopoietic Syndromes; EZH2 gene; Epigenetic Process; Event; Exons; Funding; Gene Mutation; Genes; Genetic; Grant; Health; Hematological Disease; Hematopoiesis; Hematopoietic; Induced Mutation; Ineffective Hematopoiesis; Introns; Lesion; Messenger RNA; Missense Mutation; Modality; Modeling; Molecular; Mutate; Mutation; Nature; Pathogenicity; Patient Care; Patients; Pharmacology; Phase II Clinical Trials; Phenotype; Physicians; Point Mutation; Pre-Clinical Model; Production; Prognosis; Proteome; RNA Binding; RNA Processing; RNA Splicing; Recurrence; Risk; Role; SRSF2 gene; Scientist; Series; Site; Spliceosomes; Testing; Therapeutic; Treatment Efficacy; Work; curative treatments; disease phenotype; experimental study; feasibility testing; functional genomics; genetic association; hematopoietic stem cell self-renewal; insight; loss of function; mutant; new therapeutic target; novel; preference; small molecule; therapeutic evaluation; transcriptome

SUMMARY Mutations in genes encoding RNA splicing factors are the most common class of genetic alterations in myelodysplastic syndromes (MDS), a group of blood disorders that are characterized by clonal, dysplastic, and ineffective hematopoiesis. One of the most commonly mutated genes is SRSF2, which encodes a regulator of alternative splicing and is subject to recurrent missense mutations primarily affecting a single “hotspot” residue. During the initial funding period of this grant, work by our labs and others led to a consensus model for how SRSF2 mutations promote MDS: MDS-associated hotspot SRSF2 mutations alter SRSF2’s RNA-binding affinity, driving mis-splicing of key hematopoietic regulators to cause dysplastic hematopoiesis. Importantly, SRSF2 mutations may confer therapeutically actionable vulnerabilities. We identified specific compounds that modulate RNA splicing to preferentially kill SRSF2-mutant cells over their wild-type counterparts, helping to motivate the earliest clinical trials of new drugs targeting MDS with splicing factor mutations. Here, we propose to refine and extend our current understanding of SRSF2 mutations. While useful, our current model is not sufficient to fully explain the genetic spectrum of SRSF2 mutations, interactions between SRSF2 mutations and other co-occurring genetic lesions, and the functional roles and therapeutic implications of SRSF2 mutations in MDS. Our interdisciplinary team consists of a physician-scientist with expertise in MDS and patient care (Abdel-Wahab) and a basic scientist with expertise in RNA splicing and functional genomics (Bradley). In preliminary studies, we identified diverse phenomena that are not explained by our current model of SRSF2 mutations: rare, non-hotspot SRSF2 mutations may be pathogenic; although multiple co-occurring splicing factor mutations are generally thought to be incompatible with cell survival, a subset of MDS patients carry two such mutations; SRSF2 mutations cause profound changes in RNA processing beyond mis-splicing of cassette exons; and SRSF2 mutations induce sensitivity to multiple classes of compounds that modulate RNA splicing via distinct mechanisms of action. We propose to build on these preliminary studies as follows: Aim 1, Determine the molecular basis and functional consequences of widespread intron retention in SRSF2- mutant MDS; Aim 2, Determine the biological and molecular basis for allele-specific interactions between SRSF2 mutations and additional genetic alterations in MDS; Aim 3, Identify and test therapeutic strategies for targeting cells with spliceosomal gene mutations. The significance of these studies is that they will give insight into the molecular and functional basis for SRSF2 mutations in MDS. The health relatedness of this effort is that the proposed work may identify new treatment modalities that specifically target SRSF2-mutant MDS, which is associated with particularly poor prognosis.

概括 编码 RNA 剪接因子的基因突变是最常见的一类遗传改变。 骨髓增生异常综合征 (MDS) 是一组以克隆性、发育不良和骨髓增生异常为特征的血液疾病 最常见的突变基因之一是 SRSF2，它编码一个调节因子。 选择性剪接，并且容易发生主要影响单个“热点”残基的反复错义突变。 在这笔赠款的初始资助期间，我们的实验室和其他人的工作就如何达成共识模型 SRSF2 突变促进 MDS：MDS 相关热点 SRSF2 突变改变 SRSF2 的 RNA 结合 亲和力，驱动关键造血调节因子的错误剪接，导致造血发育不良。 SRSF2 突变可能会带来治疗上可行的弱点。 调节 RNA 剪接以优先杀死 SRSF2 突变细胞而不是其野生型盟友，从而有助于 推动针对具有剪接因子突变的 MDS 的新药进行最早的临床试验。 在这里，我们建议完善和扩展我们目前对 SRSF2 突变的理解。 目前的模型不足以充分解释 SRSF2 突变的遗传谱、突变之间的相互作用 SRSF2 突变和其他同时发生的遗传病变及其功能作用和治疗意义 我们的跨学科团队由一位具有 MDS 专业知识的医师科学家组成。 和患者护理 (Abdel-Wahab) 以及一位在 RNA 剪接和功能基因组学方面具有专业知识的基础科学家 （布拉德利）在初步研究中，我们发现了当前模型无法解释的多种现象。 SRSF2 突变：罕见的非热点 SRSF2 突变可能具有致病性，尽管多种同时发生； 剪接因子突变通常被认为与细胞存活（MDS 患者的一个子集）不相容 携带两个这样的突变；除了错误剪接之外，SRSF2 突变还会导致 RNA 加工发生深刻的变化。 盒外显子的数量；SRSF2 突变诱导对多种调节化合物的敏感性 我们建议在这些初步研究的基础上进行如下的 RNA 剪接： 目标 1，确定 SRSF2- 中广泛内含子保留的分子基础和功能后果 突变 MDS；目标 2，确定等位基因特异性相互作用的生物学和分子基础 MDS 中的 SRSF2 突变和其他基因改变；目标 3，确定并测试 MDS 的治疗策略 这些研究的意义在于它们将提供见解。 研究 MDS 中 SRSF2 突变的分子和功能基础。这项工作的健康相关性是。 拟议的工作可能会确定专门针对 SRSF2 突变型 MDS 的新治疗方式， 这与特别不良的预后有关。