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：
Golam Mohi
金额：
$ 58.14万
依托单位：
UNIVERSITY OF VIRGINIA
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：
https://reporter.nih.gov/project-details/10649974
关键词：
3&apos Splice Site Acute Myelocytic Leukemia Address Anemia Animal Model Applications Grants Binding Biological Biological Assay Bone Marrow Cell Cycle Checkpoint Cell model Cells Characteristics DNA Damage DNA biosynthesis DNMT3a Data Dysmyelopoietic Syndromes Dysplasia EZH2 gene Ectopic Expression Epigenetic Process Erythroid Gene Expression Gene Mutation Genes Genetic Transcription Goals Hematologic Neoplasms Hematological Disease Hematopoiesis Hematopoietic Hematopoietic stem cells Heterozygote Knock-in Mouse Length MAP Kinase Gene MAP3K7 gene Macrocytic Anemia Mitogen-Activated Protein Kinase Inhibitor Molecular Mus Mutant Strains Mice Mutation Myelogenous Myeloid Cells Neutropenia Pathogenesis Patients Play Protein Isoforms RNA RNA Splicing Regulator Genes Risk Role SRSF2 gene Somatic Mutation Specificity Spliced Genes Spliceosomes TGF Beta Signaling Pathway TGFBR2 gene Testing Thrombocytopenia Transcript U2 Small Nuclear Ribonucleoprotein Zinc Fingers bone marrow failure syndrome cytopenia driver mutation expectation hematopoietic stem cell expansion in vivo inhibitor insight knock-down mRNA Precursor mutant new therapeutic target novel novel therapeutic intervention p38 Mitogen Activated Protein Kinase progenitor proteogenomics recruit replication stress response self-renewal synergism therapeutic evaluation

3&apos Splice Site Acute Myelocytic Leukemia Address Anemia Animal Model Applications Grants Binding Biological Biological Assay Bone Marrow Cell Cycle Checkpoint Cell model Cells Characteristics DNA Damage DNA biosynthesis DNMT3a Data Dysmyelopoietic Syndromes Dysplasia EZH2 gene Ectopic Expression Epigenetic Process Erythroid Gene Expression Gene Mutation Genes Genetic Transcription Goals Hematologic Neoplasms Hematological Disease Hematopoiesis Hematopoietic Hematopoietic stem cells Heterozygote Knock-in Mouse Length MAP Kinase Gene MAP3K7 gene Macrocytic Anemia Mitogen-Activated Protein Kinase Inhibitor Molecular Mus Mutant Strains Mice Mutation Myelogenous Myeloid Cells Neutropenia Pathogenesis Patients Play Protein Isoforms RNA RNA Splicing Regulator Genes Risk Role SRSF2 gene Somatic Mutation Specificity Spliced Genes Spliceosomes TGF Beta Signaling Pathway TGFBR2 gene Testing Thrombocytopenia Transcript U2 Small Nuclear Ribonucleoprotein Zinc Fingers bone marrow failure syndrome cytopenia driver mutation expectation hematopoietic stem cell expansion in vivo inhibitor insight knock-down mRNA Precursor mutant new therapeutic target novel novel therapeutic intervention p38 Mitogen Activated Protein Kinase progenitor proteogenomics recruit replication stress response self-renewal synergism therapeutic evaluation

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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：U2AF1突变引起的骨髓增生的分子基础抽象的骨髓增生综合征（MDS）是克隆血液学疾病，其特征是细胞质和发育不良髓样线素细胞的转化风险增加到急性髓样白血病。当前疗法不足以治疗MD。这强调了更好地了解MDS的分子机制的需求并确定MDS中的新治疗靶标。编码RNA剪接因子的基因中的突变（U2AF1，，在MDS中经常观察到SRSF2，SF3B1或ZRSR2）。 U2AF1参与了对3'的识别在MRNA剪接期间募集U2 SNRNP所需的剪接位点。 U2AF1突变已经在〜11％的MDS病例中确定。但是，U2AF1突变在MDS和 U2AF1突变导致MDS发病机理的机制尚不清楚。确定突变体U2AF1在MDS中的作用，我们产生了一种新的条件U2AF1-Q157R敲入小鼠。在初步研究，我们观察到U2AF1-Q157R突变体的造血表达导致大细胞性贫血，红细胞发育不良和造血干细胞（HSC）在骨髓中的扩张。我们还观察到，EZH2的并发损失和U2AF1-Q157R突变体的表达促进了快速 MD的进展。我们假设U2AF1突变触发RNA剪接改变，基因表达 HSPC的变化，DNA损伤和复制应力导致异常造血，U2AF1 MDS进展中的表观遗传调节剂突变合作。为了检验我们的假设，我们提案三个具体目标。在AIM 1中，我们将研究U2AF1-Q157R突变的后果和骨髓增生性的基本分子机制。在AIM 2中，我们将确定生物学和分子 U2AF1突变与同时出现的表观遗传调节剂突变之间的协同作用的基础 MD的发病机理。在AIM 3中，我们将确定和测试U2AF1突变体MD的治疗策略。结果从这些研究中，将为MDS的分子发病机理提供新的见解，并可能导致新的见解治疗MD的治疗方法。