The Molecular and Biochemical Function of SAMD9 and SAMD9L in Pediatric MDS

SAMD9 和 SAMD9L 在儿科 MDS 中的分子和生化功能

• 批准号: 10249947
• 负责人: Melvin Edward Thomas
• 金额: $ 6.86万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10249947
• 关键词: Affect; Binding; Biochemical; Biological Assay; Bone Marrow; CRISPR/Cas technology; Cell division; Cell physiology; Cells; Cellular biology; Child; Childhood; Chromosome 7; Complex; Computer Models; DNA Repair Pathway; Data; Development; Disease; Disease Progression; Dysmyelopoietic Syndromes; Experimental Models; Foundations; Functional disorder; Genes; Germ-Line Mutation; Goals; Growth; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Human; Human Chromosomes; Hypocellular Bone Marrow; Immunoprecipitation; Impairment; Inflammation; Inflammatory; Interferons; Knowledge; Label; Lead; Mediating; Missense Mutation; Modeling; Molecular; Molecular Structure; Monosomy 7; Mutation; Myeloproliferative disease; Nature; Pathogenicity; Patients; Phenotype; Play; Proteins; Proteomics; RNA Transport; Recurrence; Reporting; Research; Research Training; Resources; Ribosomal RNA; Role; SAM Domain; Saint Jude Children' s Research Hospital; Secondary to; Series; Stimulus; Stress; Structural Biochemistry; Structure; Susceptibility Gene; Tertiary Protein Structure; Testing; Training; apoptotic protease-activating factor 1; base; cell growth; collaborative environment; cytopenia; disease phenotype; insight; interdisciplinary approach; mutant; novel strategies; nucleoside triphosphatase; paralogous gene; peripheral blood; pressure; protein complex; protein function; protein protein interaction

Project Summary: Myelodysplastic syndrome (MDS) is a heterogeneous group of diseases affecting hematopoietic stem cells. Children with this disorder have impaired hematopoiesis resulting in peripheral blood cytopenias, hypocellular bone marrows, and are frequently associated with chromosome 7 deletions (monosomy 7). We recently identified heterozygous germline mutations in sterile alpha motif (SAM) domain-9 (SAMD9) and its paralog, SAMD9-like (SAMD9L) in children with monosomy 7 mediated MDS. Surprisingly, the monosomy 7 clone that expands in the bone marrow universally lacks the germline mutation suggesting there is strong selective pressure against the growth of hematopoietic stem cells expressing the mutant proteins. Expression of SAMD9 and SAMD9L is induced by interferons and other inflammatory stimuli and causes reduced cell division and cell growth. Most pathogenic mutations found in patients dramatically enhance these effects, exaggerating the anti- proliferative effects. Our data strongly suggest that SAMD9 and SAMD9L play an important role in pediatric MDS, but there is an inadequate understanding of the cellular and biochemical function of these proteins. The rigor of these findings provides a strong scientific premise to investigate the molecular and biochemical function of these proteins in order to understand their functional role in the development of MDS with monosomy 7. I hypothesize that the hematopoietic cell growth suppression resulting from the expression of mutant SAMD9 or SAMD9L is secondary to changes their protein-protein interaction networks and biochemical function preceding Monosomy 7 development. I will test these hypotheses in the following specific aims using human hematopoietic cells. In specific aim 1, I will test the hypothesis that protein-protein interactions of SAMD9 and SAMD9L play a regulatory role in hematopoietic cell growth. In specific aim 2, I will define the biochemical structure and function of SAMD9 and SAMD9L domain(s) necessary for the inhibition of cellular growth. We don’t know the mechanism(s) SAMD9 and SAMD9L employ that leads to the selection of monosomy 7 cells which can progress to MDS. My proposed studies aim to fill these knowledge gaps and will ultimately help drive the field of pediatric MDS research forward, potentially leading to new approaches for the treatment of children with germline SAMD9 and SAMD9L mutations.

项目总结： 骨髓增生异常综合征(MDS)是一组影响造血干细胞的异质性疾病。 患有这种疾病的儿童造血功能受损，导致外周血细胞减少、细胞减少 骨髓，并经常与7号染色体缺失(单体7)相关。我们最近 鉴定了不育α基序(SAM)结构域9(SAMD9)及其同源基因的杂合胚系突变， 7号单体介导的MDS患儿中的SAMD9样蛋白(SAMD9L)。令人惊讶的是，单体7克隆了 在骨髓中普遍缺乏胚系突变，提示有较强的选择性 抑制表达突变蛋白的造血干细胞生长的压力。SAMD9基因的表达 而SAMD9L由干扰素和其他炎症刺激诱导，导致细胞分裂和细胞减少 成长。在患者中发现的大多数致病基因突变都显著增强了这些影响，夸大了抗 增殖效应。我们的数据有力地表明SAMD9和SAMD9L在儿科疾病中起着重要作用 MDS，但对这些蛋白质的细胞和生化功能了解不足。这个 这些发现的严谨性为研究分子和生化提供了强有力的科学前提。 这些蛋白的功能，以了解它们在MDS的发生发展中的功能作用 单体7。我假设造血细胞生长抑制是由于表达了 突变体SAMD9或SAMD9L继发于其蛋白质-蛋白质相互作用网络和生化改变 功能先于单体7开发。我将在以下特定目标中测试这些假设 人类造血细胞。在特定的目标1中，我将测试以下假设： SAMD9和SAMD9L在造血细胞生长中起调节作用。在具体目标2中，我将定义 抑制细胞生长所必需的SAMD9和SAMD9L结构域(S)的生化结构和功能 成长。我们不知道(S)SAMD9和SAMD9L采用的机制是导致选择 可进展为MDS的单体7细胞。我提议的研究旨在填补这些知识空白，并将 最终有助于推动儿科MDS研究领域向前发展，可能导致新的方法 生殖系SAMD9和SAMD9L突变儿童的治疗。