Cellular and functional impact of SAMD9L mutations on hematopoiesis and myelodysplasia

SAMD9L 突变对造血和骨髓增生异常的细胞和功能影响

• 批准号: 10541172
• 负责人: Jeffery M Klco
• 金额: $ 44.88万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10541172
• 关键词: Acute Myelocytic Leukemia; Address; Adult; Affect; Alleles; Aneuploidy; Biological Assay; Biology; Bone Marrow; CD34 gene; Cell Differentiation process; Cells; Cellular Stress; Child; Childhood; Chromosome 7; Clinical; Clinical Management; Collaborations; Complex; Curiosities; Data; Development; Disease; Dysmyelopoietic Syndromes; Event; Excision; Experimental Models; Family; Family Planning; Frequencies; Future; Gene Expression; Genes; Genetic; Genomics; Germ-Line Mutation; Goals; Growth; Growth and Development function; Hematology; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Heterozygote; Human; In Vitro; Interferon alpha; Interferons; Investigation; Knowledge; Malignant Neoplasms; Missense Mutation; Modeling; Monosomy 7; Mus; Mutation; Myelogenous; Myeloproliferative disease; Outcome; Pathogenicity; Pathway interactions; Patients; Phenotype; Process; Prognosis; Protein Region; Proteins; Role; Signal Transduction; Stress; Structure; Syndrome; Testing; Virus Diseases; Work; cell growth; chromosome 7 loss; chromosome loss; clinical phenotype; cohort; environmental stressor; human cord blood CD34+ cell; in vitro testing; in vivo; insight; lentivirally transduced; mutant; overexpression; pediatric myelodysplastic syndrome; response; self-renewal; tissue/cell culture; tool; transcriptome sequencing

PROJECT SUMMARY: The development of a myelodysplastic syndrome (MDS) is a multistep process involving disease initiation, clonal progression with acquisition of cooperating mutations and a complex interplay with the microenvironment. In this proposal, we will focus specifically on the initial event in this pathway that ultimately leads to loss of chromosome 7 and MDS in children. Through our recent studies on pediatric MDS, we identified germline heterozygous mutations in two interferon-inducible genes on chromosome 7-SAMD9 and SAMD9L-that result in growth suppression when exogenously expressed in tissue culture cells and are associated with monosomy 7 in children with a range of different myeloid abnormalities. Curiously, the copy of chromosome 7 that is lost in these patients universally is the copy that harbors the mutant allele. Thus, it appears that in this context, monosomy 7 is an adaptation to the cellular effect of these mutations and while likely providing a mechanism for hematopoietic cells to grow in these patients, the loss of one copy of chromosome 7 can lead to MDS or other hematopoietic abnormalities. These genomic and clinical findings establish a strong scientific premise to investigate the cellular and functional impacts of SAMD9L mutations in human and mouse hematopoietic cells with a long-term goal to understand how these mutations can ultimately lead to MDS with monosomy 7. We hypothesize that expression of mutant SAMD9L decreases hematopoietic cell growth and differentiation, and that different SAMD9L alleles can cooperate with cell intrinsic or extrinsic factors to influence hematopoietic phenotypes. We will test our hypothesis with the following specific aims using a combination of genetic tools and functional assays in human and mouse hematopoietic cells. Specific Aim 1: We will test the in vitro impact of different SAMD9L mutations in primary hematopoietic cells. Specific Aim 2: We will determine the effect of Samd9l alleles on self-renewal and transformation. Specific Aim 3: We will test the contribution of environmental stress and SAMD9L expression on hematopoietic cell growth and differentiation in human cells. The identification of germline mutations in SAMD9 or SAMD9L in children with MDS is a significant advancement in the field of pediatric myeloid neoplasms. Our proposed studies will define the role of both mutant and wild-type SAMD9L in hematopoiesis, the results of which will ultimately impact how patients with these mutations are clinically managed. Not only will this proposal significantly enhance our knowledge of SAMD9L biology, but we will broadly address how chromosomal aneuploidy can be an adaptive response to cellular stresses, which is likely a shared mechanism across different developmental abnormalities or cancers.

项目概要： 骨髓增生异常综合征（MDS）的发展是一个涉及疾病起始的多步骤过程， 克隆进展与收购合作突变和复杂的相互作用， 微环境。在本提案中，我们将特别关注这一途径中的初始事件， 导致儿童7号染色体丢失和MDS。通过我们最近对小儿MDS的研究，我们 在染色体7-SAMD 9上的两个干扰素诱导基因中鉴定出生殖系杂合突变， SAMD 9 L-当在组织培养细胞中外源表达时导致生长抑制， 在患有一系列不同骨髓异常的儿童中与7号单体性相关。奇怪的是， 在这些患者中普遍丢失的7号染色体的拷贝是携带突变等位基因的拷贝。因此 在这种情况下，单体7似乎是对这些突变的细胞效应的适应，而 这可能为造血细胞在这些患者中生长提供了一种机制， 7号染色体可导致MDS或其它造血异常。这些基因组和临床发现 建立强有力的科学前提，以研究SAMD 9 L突变对细胞和功能的影响 在人类和小鼠造血细胞中，长期目标是了解这些突变如何 最终导致具有单体7的MDS。我们假设突变型SAMD 9 L的表达降低， 造血细胞生长和分化，且不同SAMD 9 L等位基因可与细胞协同作用 影响造血表型的内在或外在因素。我们将测试我们的假设与 在人类和小鼠中使用遗传工具和功能测定的组合， 造血细胞具体目标1：我们将测试不同SAMD 9 L突变在原发性肝癌中的体外影响。 造血细胞具体目标2：我们将确定Samd 91等位基因对自我更新的影响， 转型具体目标3：我们将测试环境胁迫和SAMD 9 L表达的贡献 造血细胞的生长和分化。生殖系突变的鉴定 SAMD 9或SAMD 9 L在MDS儿童中的应用是儿科骨髓移植领域的重大进展。 肿瘤。我们提出的研究将确定突变型和野生型SAMD 9 L在造血中的作用， 其结果将最终影响如何对这些突变患者进行临床管理。不仅 这项提议是否会大大提高我们对SAMD 9 L生物学的认识，但我们将广泛地讨论如何 染色体非整倍性可能是对细胞应激的适应性反应，这可能是一种共同的遗传反应。 不同发育异常或癌症的机制。

项目成果

Pediatric MDS and bone marrow failure-associated germline mutations in SAMD9 and SAMD9L impair multiple pathways in primary hematopoietic cells.

• DOI: 10.1038/s41375-021-01212-6
• 发表时间: 2021-11
• 期刊: Leukemia
• 影响因子: 11.4
• 作者: Thomas ME 3rd;Abdelhamed S;Hiltenbrand R;Schwartz JR;Sakurada SM;Walsh M;Song G;Ma J;Pruett-Miller SM;Klco JM
• 通讯作者: Klco JM

The genomic landscape of pediatric myelodysplastic syndromes.

• DOI: 10.1038/s41467-017-01590-5
• 发表时间: 2017-11-16
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Schwartz JR;Ma J;Lamprecht T;Walsh M;Wang S;Bryant V;Song G;Wu G;Easton J;Kesserwan C;Nichols KE;Mullighan CG;Ribeiro RC;Klco JM
• 通讯作者: Klco JM