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The Role of DDX41 in Inherited Myelodysplastic Syndromes

DDX41 在遗传性骨髓增生异常综合征中的作用

基本信息

批准号：
9804068
负责人：
Timothy Michael Chlon
金额：
$ 10.95万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9804068
关键词：
Acute Myelocytic Leukemia Adult Affinity Alleles Amino Acid Substitution Binding Biochemical Biogenesis Biological Assay Blood Cell Cycle Progression Cell Death Cell Differentiation process Cell physiology Cells DNA Damage DNA Modification Methylases DNA biosynthesis DNMT3a Data Defect Development Disease Dysmyelopoietic Syndromes Dysplasia Embryo Frameshift Mutation Functional disorder Genetic Diseases Genomic Instability Germ-Line Mutation Goals Growth Helicase Gene Hematologic Neoplasms Hematological Disease Hematopoiesis Hematopoietic Hematopoietic stem cells Heterozygote Homeostasis Host Defense Human Immune Immune signaling Impairment In Vitro Incidence Individual Ineffective Hematopoiesis Infection Inherited Knock-out Lead Leukemic Cell Link Malignant - descriptor Malignant Neoplasms Missense Mutation Modeling Molecular Monitor Mus Mutation Myelogenous Pathogenesis Patients Phenotype Proteins Proteomics RNA Helicase RNA Splicing Ribosomes Role Somatic Mutation Testing Transplantation Virus Replication aging population cytopenia disease-causing mutation hematopoietic stem cell self-renewal high risk in vivo loss of function malignant phenotype mutant new therapeutic target novel self-renewal sensor small hairpin RNA targeted treatment therapeutic target

项目摘要

Project Summary Myelodysplastic syndromes (MDS) are genetic disorders caused by impaired hematopoietic stem/progenitor cells (HSPC), which can transform to acute myeloid leukemia (AML). MDS typically occurs in the ageing population, however MDS can also manifest as a result of inherited germline mutations in younger individuals. Mutations in the DEAD/H-box helicase gene DDX41 are among the most common alterations associated with inherited MDS. Inherited DDX41 mutations are heterozygous and are typically frameshifts, suggesting that these mutations result in loss of DDX41 function. DDX41 mutations are also observed in de novo MDS and AML, and are typically missense mutations frequently resulting in the amino acid substitution R525H. DDX41 is an RNA helicase that hydrolyzes ATP, and can function as an innate immune sensor, RNA splicing factor, and ribosome regulator. The precise mechanism(s) by which DDX41 mutations alter HSPC function and contribute to MDS/AML remains unknown. As such, the proposed project will define the role of DDX41 mutations in the pathogenesis of MDS/AML. To mimic the frameshift mutations observed in human MDS and determine the role of DDX41 in normal hematopoiesis, we generated hematopoietic-specific and conditional Ddx41-deficient mice. Our preliminary data has revealed that DDX41-deficiency (complete knockout) is not compatible with HSPC function and hematopoiesis, whereas DDX41 heterozygosity increases BM HPSC. In addition, through integrative proteomic and biochemical approaches we identified a novel DDX41-interacting protein in leukemic cells, SAMHD1, a dNTPase and host defense factor, which controls cellular pools of dNTPs. Collectively, our preliminary data indicate that DDX41 has a critical role in hematopoiesis and HSPC function. We hypothesize that diminished DDX41 expression and/or function contributes to ineffective hematopoiesis and to the pathogenesis of MDS and AML, in part due to increased SAMHD1 activity and altered cellular dNTP pools. Therefore, the objectives of this proposal are to model somatic and germline DDX41 mutations in normal and malignant hematopoiesis, and to elucidate the molecular function of DDX41 required for HSPC function. Through extensive hematopoietic approaches, we will define the role of DDX41 deficiency and R525H expression in MDS incidence and progression to AML (Aim 1). Since DNMT3A and DDX41 mutations commonly co-occur in MDS patients that have progressed to AML, we will determine whether DDX41 heterozygosity or R525H expression combined with DNMT3A-deficient mice will result in high-risk MDS or overt AML. Reduced cellular dNTP pools impair cell cycle progression and result in genomic instability; therefore, we will determine the role of SAMHD1 activity in DDX41-deficient HSPC or mutant MDS, and whether diminished cellular dNTPs pools lead to genomic instability and development of AML (Aim 2). By elucidating the function of DDX41 malignant hematopoiesis, we predict to uncover novel mechanisms underlying inherited and de novo MDS.

项目总结