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Uncovering the Role of the DEAD Box Helicase Ddx41 in Hematopoiesis

揭示 DEAD Box 解旋酶 Ddx41 在造血中的作用

基本信息

批准号：
10212445
负责人：
Joshua Weinreb
金额：
$ 5.1万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-16 至 2022-07-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10212445
关键词：
AML/MDS Acute Myelocytic Leukemia Address Affect Anemia Animal Model Blood Blood Cells Cell Line Cells Clinical Co-Immunoprecipitations Complex Data Defect Development Developmental Biology Disease Dysmyelopoietic Syndromes Elderly Embryo Erythropoiesis Event Functional disorder Genes Genetic Germ-Line Mutation Goals Hematologic Neoplasms Hematological Disease Hematology Hematopoiesis Hematopoietic Hematopoietic System Hematopoietic stem cells High-Throughput Nucleotide Sequencing In Situ Hybridization Lead Mediating Messenger RNA Modeling Molecular Molecular Biology Techniques Mutate Mutation Myelopoiesis Neutropenia Outcome Pancytopenia Pathogenesis Pathway interactions Patients Phenotype Population Process Proteins RNA Splicing Regulation Role Sampling Somatic Mutation Spliceosomes Stains Structure Techniques Testing Training Transgenic Organisms Work Zebrafish advanced disease bone marrow failure syndrome cell growth cell type cytopenia experimental study helicase in vivo in vivo Model insight knock-down leukemogenesis loss of function mutant neoplastic cell novel novel therapeutic intervention premalignant

项目摘要

Abstract Myelodysplastic syndromes (MDS), a group of pre-malignant bone marrow failure syndromes arising from defects in hematopoietic stem cells (HSCs), are amongst the most common hematological malignancies of the elderly with ~30% progressing to acute myeloid leukemia (AML). Recently, loss-of-function germline and somatic mutations in the DEAD-box Helicase 41 gene (DDX41) have been identified in patients with MDS and AML, and are thought to contribute to disease pathogenesis. Both germline and somatic DDX41 mutations are thought to promote hematopoietic deregulation and leukemogenesis. Although a strong clinical correlation is found between mutations in DDX41 and MDS, the in vivo role of DDX41 in hematopoiesis has not been elucidated. To address this question, we will characterize hematopoiesis in a zebrafish ddx41 loss-of-function mutant. Our preliminary studies indicate that ddx41 mutants develop neutropenia and anemia. This animal model will allow us to elucidate the in vivo role of Ddx41 in normal hematopoiesis and the underlying mechanism for any defects. DDX41 has been implicated in splicing and shown to associate with components of the spliceosome including Splicing Factor 3B, subunit 1 (SF3B1), the most commonly mutated splicing factor in MDS. Additionally, MDS/AML patient samples with DDX41 mutations displayed errors in mRNA splicing that typically occur when components of the spliceosome are defective. Although these data point towards a role for DDX41 in splicing, it is still unknown if splicing aberrations contribute to the observed abnormalities in DDX41-mutated hematologic diseases. Using ddx41-deficient zebrafish will permit us to delineate the functionally relevant early molecular events leading to blood cell defects when ddx41 is mutated, which is anticipated to provide novel insight into the origins of MDS. In this proposal, we will use our novel in vivo model of Ddx41-deficiency to test the hypothesis that Ddx41 is critical for normal hematopoiesis via regulation of splicing, and that malfunctioning of this process contributes to the hematological defects seen in DDX41- mutated MDS/AML. In Aim 1, we will determine which blood populations require Ddx41 and which functional domains of Ddx41 are required for healthy hematopoiesis. In Aim 2, we will elucidate connections between DDX41 and SF3B1 using protein and genetic interaction studies. Combined these studies will reveal insights into the pathophysiology of DDX41-mutated MDS/AML.

摘要骨髓增生异常综合征(MDS)，一组由造血干细胞(HSCs)缺陷是最常见的血液系统恶性肿瘤之一。约30%的老年人进展为急性髓系白血病(AML)。最近，功能丧失的生殖系和死亡盒解旋酶41基因(DDX41)在MDS和MDS患者中被发现存在体细胞突变 AML，并被认为与疾病的发病机制有关。种系和体细胞DDX41突变都是被认为促进了造血系统的去调节和白血病的发生。尽管有很强的临床相关性在发现DDX41和MDS突变之间，DDX41在体内的造血作用尚未得到证实已澄清。为了解决这个问题，我们将描述一条功能丧失的斑马鱼ddx41的造血功能。变种人。我们的初步研究表明，ddx41突变体会出现中性粒细胞减少症和贫血。这只动物模型将使我们能够阐明Ddx41在正常造血中的体内作用以及潜在的任何缺陷的机械装置。DDX41与剪接有关，并被证明与组件有关剪接小体包括剪接因子3B亚基1(SF3B1)，是最常见的突变剪接因子在MDS中。此外，带有DDX41突变的MDS/AML患者样本在mRNA剪接中显示出错误通常发生在剪接体的组件有缺陷时。尽管这些数据指向一个角色对于DDX41在剪接中，是否剪接像差导致观察到的异常仍然是未知的。 DDX41-突变的血液病。使用ddx41基因缺失的斑马鱼将使我们能够描绘出当ddx41突变时，导致血细胞缺陷的功能相关的早期分子事件，这是期望为MDS的起源提供新的见解。在这个提案中，我们将使用我们的小说在体内 Ddx41缺乏症模型验证Ddx41通过调节对正常造血至关重要的假说剪接过程的故障导致了DDX41的血液学缺陷- 突变的MDS/AML。在目标1中，我们将确定哪些血液群体需要Ddx41，哪些功能 Ddx41的结构域是健康造血所必需的。在目标2中，我们将阐明利用蛋白质和遗传互作研究DDX41和SF3B1。将这些研究结合在一起将揭示出探讨DDX41突变MDS/AML的病理生理机制。