Molecular Basis for Myelodysplasia Induced by U2AF1 Mutations
U2AF1 突变诱导的骨髓增生异常的分子基础
基本信息
- 批准号:10649974
- 负责人:
- 金额:$ 58.14万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-06-15 至 2027-05-31
- 项目状态:未结题
- 来源:
- 关键词:3&apos Splice SiteAcute Myelocytic LeukemiaAddressAnemiaAnimal ModelApplications GrantsBindingBiologicalBiological AssayBone MarrowCell Cycle CheckpointCell modelCellsCharacteristicsDNA DamageDNA biosynthesisDNMT3aDataDysmyelopoietic SyndromesDysplasiaEZH2 geneEctopic ExpressionEpigenetic ProcessErythroidGene ExpressionGene MutationGenesGenetic TranscriptionGoalsHematologic NeoplasmsHematological DiseaseHematopoiesisHematopoieticHematopoietic stem cellsHeterozygoteKnock-in MouseLengthMAP Kinase GeneMAP3K7 geneMacrocytic AnemiaMitogen-Activated Protein Kinase InhibitorMolecularMusMutant Strains MiceMutationMyelogenousMyeloid CellsNeutropeniaPathogenesisPatientsPlayProtein IsoformsRNARNA SplicingRegulator GenesRiskRoleSRSF2 geneSomatic MutationSpecificitySpliced GenesSpliceosomesTGF Beta Signaling PathwayTGFBR2 geneTestingThrombocytopeniaTranscriptU2 Small Nuclear RibonucleoproteinZinc Fingersbone marrow failure syndromecytopeniadriver mutationexpectationhematopoietic stem cell expansionin vivoinhibitorinsightknock-downmRNA Precursormutantnew therapeutic targetnovelnovel therapeutic interventionp38 Mitogen Activated Protein Kinaseprogenitorproteogenomicsrecruitreplication stressresponseself-renewalsynergismtherapeutic evaluation
项目摘要
Title: Molecular Basis for Myelodysplasia Induced by U2AF1 Mutations
Abstract
Myelodysplastic syndromes (MDS) are clonal hematologic disorders characterized by cytopenia and dysplasia
of myeloid linage cells with an increased risk of transformation to acute myeloid leukemia. Current therapies
are inadequate to treat MDS. This underscores a need to better understand the molecular mechanism of MDS
and identify new therapeutic targets in MDS. Mutations in the genes encoding RNA splicing factors (U2AF1,
SRSF2, SF3B1 or ZRSR2) are frequently observed in MDS. U2AF1 is involved in the recognition of the 3’
splice site required for recruitment of the U2 snRNP during pre-mRNA splicing. U2AF1 mutations have been
identified in ~11% cases of MDS. However, the functional roles of U2AF1 mutations in MDS and the
mechanism by which U2AF1 mutations contribute to MDS pathogenesis remain unclear. To determine the
roles of mutant U2AF1 in MDS, we have generated a novel conditional U2AF1-Q157R knock-in mouse. In
preliminary studies, we have observed that hematopoietic expression of U2AF1-Q157R mutant results in a
macrocytic anemia, erythroid dysplasia and expansion of hematopoietic stem cells (HSC) in the bone marrow.
We also have observed that concurrent loss of EZH2 and expression of U2AF1-Q157R mutant promotes rapid
progression of MDS. We hypothesize that U2AF1 mutations trigger RNA splicing alterations, gene expression
changes, DNA damage and replication stress in HSPC leading to aberrant hematopoiesis, and U2AF1
mutations cooperate with epigenetic regulator mutations in the progression of MDS. To test our hypothesis, we
propose three Specific Aims. In Aim 1, we will investigate the consequences of U2AF1-Q157R mutation and
underlying molecular mechanisms in myelodysplasia. In Aim 2, we will determine the biological and molecular
basis for synergy between U2AF1 mutations and co-occurring epigenetic regulator mutations in the
pathogenesis of MDS. In Aim 3, we will identify and test therapeutic strategies for U2AF1 mutant MDS. Results
from these studies will provide new insights into the molecular pathogenesis of MDS and may lead to new
therapeutic approach for treatment of MDS.
标题:U2 AF 1突变诱导的骨髓增生异常的分子基础
摘要
骨髓增生异常综合征(MDS)是一种以血细胞减少和发育异常为特征的克隆性血液病
髓系细胞转化为急性髓系白血病的风险增加。当前疗法
不足以治疗MDS。这强调了需要更好地了解MDS的分子机制
并确定MDS的新治疗靶点。编码RNA剪接因子(U2 AF 1,
SRSF 2、SF 3B 1或ZRSR 2)在MDS中经常观察到。U2 AF 1参与3'端的识别,
前体mRNA剪接过程中募集U2 snRNP所需的剪接位点。U2 AF 1突变已被
在约11%的MDS病例中确定。然而,U2 AF 1突变在MDS中的功能作用和
U2 AF 1突变导致MDS发病的机制尚不清楚。确定
为了研究突变型U2 AF 1在MDS中的作用,我们已经产生了一种新的条件性U2 AF 1-Q157 R基因敲入小鼠。在
初步研究中,我们观察到U2 AF 1-Q157 R突变体的造血表达导致了一种新的造血抑制因子,
巨红细胞性贫血、红细胞发育不良和骨髓中造血干细胞(HSC)扩增。
我们还观察到EZH 2的同时缺失和U2 AF 1-Q157 R突变体的表达促进了EZH 2的快速表达。
MDS的进展。我们假设U2 AF 1突变触发RNA剪接改变,基因表达
HSPC中的变化、DNA损伤和复制应激导致异常造血,以及U2 AF 1
在MDS的进展中,突变与表观遗传调节因子突变协同作用。为了验证我们的假设,我们
提出三个具体目标。在目标1中,我们将研究U2 AF 1-Q157 R突变的后果,
脊髓发育不良的潜在分子机制。在目标2中,我们将确定生物和分子
U2 AF 1突变和共同发生的表观遗传调节突变之间的协同作用的基础,
MDS的发病机制。在目标3中,我们将鉴定和测试U2 AF 1突变型MDS的治疗策略。结果
这些研究将为MDS的分子发病机制提供新的见解,并可能导致新的
用于治疗MDS的治疗方法。
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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Golam Mohi其他文献
Golam Mohi的其他文献
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Targeting of Tyrosine Phosphatase SHP2 in Myeloproliferative Neoplasms
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- 批准号:
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Role of JAK2V617F in the Pathogenesis of Myeloproliferative Neoplasms
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