Genetic and molecular basis for SRSF2 mutations in myelodysplasia

总结 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、发育异常和 无效造血最常见的突变基因之一是SRSF 2，它编码一种调节因子， 选择性剪接，并且经历主要影响单个“热点”残基的复发性错义突变。 在这项资助的最初资助期间，我们的实验室和其他人的工作导致了一个共识模型， SRSF 2突变促进MDS：MDS相关热点SRSF 2突变改变SRSF 2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。重要的是， SRSF 2突变可赋予治疗上可行的脆弱性。我们发现了一些特定的化合物， 调节RNA剪接，优先杀死SRSF 2突变细胞，而不是野生型细胞， 推动针对剪接因子突变MDS的新药的最早临床试验。 在这里，我们建议完善和扩展我们目前对SRSF 2突变的理解。虽然有用，但我们的 目前的模型不足以完全解释SRSF 2突变的遗传谱， SRSF 2突变和其他共同发生的遗传病变，以及功能作用和治疗意义 SRSF 2基因突变我们的跨学科团队由一位具有MDS专业知识的医生和科学家组成 和病人护理（阿卜杜勒-瓦哈卜）和具有RNA剪接和功能基因组学专业知识的基础科学家 （布拉德利）。在初步研究中，我们发现了目前模型无法解释的各种现象 SRSF 2突变：罕见的，非热点SRSF 2突变可能是致病的;尽管多种共同发生的 剪接因子突变通常被认为与细胞存活不相容， 携带两个这样的突变; SRSF 2突变导致RNA加工的深刻变化，而不仅仅是错误剪接 和SRSF 2突变诱导对多种类型的化合物的敏感性， 通过不同的作用机制进行RNA剪接。我们建议在这些初步研究的基础上开展以下工作： 目的1，确定SRSF 2 - 3中广泛内含子保留的分子基础和功能后果。 目的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SRSF 2突变和其他遗传改变;目的3，确定和测试 靶向剪接体基因突变的细胞。这些研究的意义在于， MDS中SRSF 2突变的分子和功能基础。这项工作的健康相关性是 这项工作可能会发现新的治疗方式，特别是针对SRSF 2突变型MDS， 这与特别差的预后有关。

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.