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.

项目摘要： 骨髓增生综合征（MDS）的发展是涉及疾病起步的多步过程， 克隆进展，通过获取合作突变以及与之复杂的相互作用 微环境。在此提案中，我们将专门关注该途径中最终的初始事件 导致儿童7染色体和MD的损失。通过我们最近关于小儿MD的研究，我们 在染色体7-SAMD9和 SAMD9L-当在组织培养细胞中外源表达并且是 与各种髓样异常的儿童中的单肌7相关。奇怪的是，副本 这些患者普遍丢失的7染色体是具有突变等位基因的副本。因此，它 看来，在这种情况下，单肌7是对这些突变的细胞效应的适应，而 在这些患者中，可能为造血细胞生长的机制提供了一种机制 7染色体可以导致MDS或其他造血异常。这些基因组和临床发现 建立强大的科学前提来研究SAMD9L突变的细胞和功能影响 在人类和小鼠造血细胞中具有长期目标，以了解这些突变如何 最终导致MDS Monsomy 7。我们假设突变体SAMD9L的表达降低 造血细胞生长和分化，并且不同的SAMD9L等位基因可以与细胞合作 影响造血表型的固有或外在因素。我们将通过 遵循特定的目的，结合了人类和小鼠中的遗传工具和功能测定 造血细胞。具体目标1：我们将测试不同SAMD9L突变在原发性中的体外影响 造血细胞。具体目标2：我们将确定SAMD9L等位基因对自我更新的影响 转型。特定目标3：我们将测试环境压力和SAMD9L表达的贡献 关于人类细胞的造血细胞生长和分化。鉴定种系突变 MDS儿童中的SAMD9或SAMD9L在小儿髓样的领域取得了重大进步 肿瘤。我们提出的研究将定义突变体和野生型SAMD9L在造血中的作用， 结果最终将影响这些突变患者的临床管理方式。不仅 该提案是否会大大增强我们对SAMD9L生物学的了解，但我们将广泛地解决如何 染色体非整倍性可能是对细胞应激的适应性反应，这可能是共同的 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