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剪接因子的基因中的突变是最常见的遗传改变 骨髓增生综合征（MDS），一组以克隆，发育不良和 无效的造血。最常见的突变基因之一是SRSF2，它编码一个调节剂 替代剪接，并受到复发的错义突变，主要影响单个“热点”住所。 在这笔赠款的最初资助期间，我们的实验室和其他人的工作导致了共识模型 SRSF2突变促进MD：与MDS相关的热点SRSF2突变改变SRSF2的RNA结合 亲和力，驱动关键造血调节剂的误导会导致发育不良的造血。重要的是， SRSF2突变可能赋予热可起作用的漏洞。我们确定了特定化合物 调节RNA剪接以优先杀死野生型的SRSF2突变细胞，从而有助于 激励针对具有剪接因子突变的MD的新药物的最早临床试验。 在这里，我们建议完善并扩展我们对SRSF2突变的当前理解。虽然有用，但我们 当前模型不足以完全解释SRSF2突变的遗传谱， SRSF2突变和其他同时发生的遗传病变以及功能作用和治疗意义 MDS中的SRSF2突变。我们的跨学科团队由一个具有MDS专业知识的身体科学家组成 和患者护理（Abdel-Wahab）和具有RNA剪接和功能基因组学专家的基础科学家 （布拉德利）。在初步研究中，我们确定了我们当前模型未解释的潜水现象 SRSF2突变：罕见的非霍茨pot Srsf2突变可能是致病性的；虽然多个同时发生 剪接因子突变通常被认为与细胞存活不相容，这是MDS患者的子集 携带两个这样的突变； SRSF2突变会导致RNA处理的深刻变化，而不是分解错误 盒式外显子； SRSF2突变会影响对调节的多种化合物的敏感性 RNA剪接通过不同的作用机理。我们建议基于这些初步研究，如下所示： AIM 1，确定宽度内含子保留在srsf2--的分子基础和功能后果 突变MD； AIM 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突变和其他遗传改变；目标3，确定和测试治疗策略 用剪接体基因突变靶向细胞。这些研究的意义在于它们将提供洞察力 进入MDS中SRSF2突变的分子和功能基础。这项工作的健康相关性是 提议的工作可能会确定专门针对SRSF2突变MD的新治疗方式， 这与预后特别不佳有关。