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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

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异常的分子基础抽象的骨髓增生异常综合征 (MDS) 是一种以血细胞减少和发育不良为特征的克隆性血液疾病髓系细胞转化为急性髓系白血病的风险增加。目前的疗法不足以治疗 MDS。这强调需要更好地了解 MDS 的分子机制并确定 MDS 的新治疗靶点。编码 RNA 剪接因子的基因突变（U2AF1、 SRSF2、SF3B1 或 ZRSR2) 在 MDS 中经常观察到。 U2AF1 参与 3’ 的识别在前 mRNA 剪接过程中招募 U2 snRNP 所需的剪接位点。 U2AF1 突变在约 11% 的 MDS 病例中发现。然而，U2AF1 突变在 MDS 中的功能作用以及 U2AF1 突变导致 MDS 发病机制尚不清楚。确定为了研究突变体 U2AF1 在 MDS 中的作用，我们构建了一种新型条件性 U2AF1-Q157R 敲入小鼠。在初步研究中，我们观察到 U2AF1-Q157R 突变体的造血表达导致大细胞性贫血、红细胞发育不良和骨髓中造血干细胞（HSC）扩张。我们还观察到 EZH2 的同时丢失和 U2AF1-Q157R 突变体的表达促进快速 MDS 的进展。我们假设 U2AF1 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造血异常，以及 U2AF1 MDS 进展中的突变与表观遗传调节突变协同作用。为了检验我们的假设，我们提出三个具体目标。在目标 1 中，我们将研究 U2AF1-Q157R 突变的后果和骨髓增生异常的潜在分子机制。在目标 2 中，我们将确定生物和分子 U2AF1突变和同时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，我们将确定并测试 U2AF1 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，并可能带来新的发现治疗MDS的治疗方法。