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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.

题目：U2AF1突变诱导骨髓发育不良的分子基础