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
基本信息
- 批准号:10241323
- 负责人:
- 金额:$ 51.96万
- 依托单位:
- 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:2015-08-01 至 2022-03-31
- 项目状态:已结题
- 来源:
- 关键词:Acute Myelocytic LeukemiaAffectAffinityAllelesAlternative SplicingAntisense OligonucleotidesAutomobile DrivingBindingBiologicalBiological Response Modifier TherapyBloodBlood CellsBone MarrowCatalysisCell SurvivalCellsClinical ResearchClinical TrialsCollaborationsComplementConsensusDiseaseDysmyelopoietic SyndromesEZH2 geneEpigenetic ProcessEventExonsFundingGene MutationGenesGeneticGrantHealthHematological DiseaseHematopoiesisHematopoieticInduced MutationIneffective HematopoiesisIntronsLesionMessenger RNAMissense MutationModalityModelingMolecularMutateMutationNaturePathogenicityPatient CarePatientsPharmacologyPhase II Clinical TrialsPhenotypePhysiciansPoint MutationPre-Clinical ModelProductionPrognosisProteomeRNA BindingRNA ProcessingRNA SplicingRecurrenceRiskRoleSRSF2 geneScientistSeriesSiteSpliceosomesTestingTherapeuticTreatment EfficacyWorkcurative treatmentsdisease phenotypeexperimental studyfeasibility testingfunctional genomicsgenetic associationhematopoietic stem cell self-renewalinsightloss of functionmutantnew therapeutic targetnovelpreferencesmall moleculetherapeutic evaluationtranscriptome
项目摘要
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.
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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Omar Abdel-Wahab其他文献
Omar Abdel-Wahab的其他文献
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{{ truncateString('Omar Abdel-Wahab', 18)}}的其他基金
Synthetic introns for selective targeting of RNA splicing factor-mutant leukemia
用于选择性靶向RNA剪接因子突变型白血病的合成内含子
- 批准号:
10722782 - 财政年份:2023
- 资助金额:
$ 51.96万 - 项目类别:
Charting the differentiation topology of SF3B1 mutated clonal hematopoiesis (CH) and myelodysplastic syndromes (MDS) via a multi-omics single-cell toolkit
通过多组学单细胞工具包绘制 SF3B1 突变克隆造血 (CH) 和骨髓增生异常综合征 (MDS) 的分化拓扑图
- 批准号:
10570240 - 财政年份:2022
- 资助金额:
$ 51.96万 - 项目类别:
Charting the differentiation topology of SF3B1 mutated clonal hematopoiesis (CH) and myelodysplastic syndromes (MDS) via a multi-omics single-cell toolkit
通过多组学单细胞工具包绘制 SF3B1 突变克隆造血 (CH) 和骨髓增生异常综合征 (MDS) 的分化拓扑图
- 批准号:
10366517 - 财政年份:2022
- 资助金额:
$ 51.96万 - 项目类别:
Project 3: Therapeutic inhibition of splicing through inhibition of protein arginine methylation in leukemia
项目3:通过抑制白血病中蛋白质精氨酸甲基化来治疗性抑制剪接
- 批准号:
10474285 - 财政年份:2021
- 资助金额:
$ 51.96万 - 项目类别:
The Memorial Sloan Kettering Cancer Center SPORE in Leukemia
纪念斯隆凯特琳癌症中心 SPORE 白血病
- 批准号:
10474261 - 财政年份:2021
- 资助金额:
$ 51.96万 - 项目类别:
Targeting an RNA Binding Protein Network in Acute Myeloid Leukemia
靶向急性髓系白血病中的 RNA 结合蛋白网络
- 批准号:
10171812 - 财政年份:2020
- 资助金额:
$ 51.96万 - 项目类别:
Interrogating the minor spliceosome to understand and treat leukemia
研究小剪接体以了解和治疗白血病
- 批准号:
10210368 - 财政年份:2020
- 资助金额:
$ 51.96万 - 项目类别:
Interrogating the minor spliceosome to understand and treat leukemia
研究小剪接体以了解和治疗白血病
- 批准号:
10434705 - 财政年份:2020
- 资助金额:
$ 51.96万 - 项目类别:
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