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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：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。