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) 的发展是一个多步骤的过程，涉及疾病起始、 克隆进展伴随着协同突变的获得以及与 微环境。在本提案中，我们将特别关注该途径中的初始事件，最终 导致儿童 7 号染色体缺失和 MDS。通过我们最近对儿科 MDS 的研究，我们 鉴定出 7 号染色体-SAMD9 上两个干扰素诱导基因的种系杂合突变 SAMD9L-在组织培养细胞中外源表达时会导致生长抑制，并且 与患有一系列不同骨髓异常的儿童的 7 号单体有关。奇怪的是，副本 这些患者普遍丢失的 7 号染色体是含有突变等位基因的副本。因此，它 似乎在这种情况下，单体 7 是对这些突变的细胞效应的适应，而 可能为这些患者的造血细胞生长提供了一种机制，丢失一个拷贝 7号染色体可导致MDS或其他造血异常。这些基因组和临床发现 建立强有力的科学前提来研究 SAMD9L 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影响 最终导致具有 7 号单体的 MDS。我们假设突变体 SAMD9L 的表达降低 造血细胞生长和分化，不同的SAMD9L等位基因可以配合细胞 影响造血表型的内在或外在因素。我们将用以下方法检验我们的假设 在人类和小鼠中结合使用遗传工具和功能测定来遵循特定目标 造血细胞。具体目标 1：我们将测试不同 SAMD9L 突变对原代细胞的体外影响 造血细胞。具体目标 2：我们将确定 Samd9l 等位基因对自我更新和 转变。具体目标3：我们将测试环境压力和SAMD9L表达的贡献 对人体细胞中造血细胞生长和分化的影响。种系突变的鉴定 SAMD9 或 SAMD9L 在儿童 MDS 中的应用是儿科骨髓细胞领域的重大进步 肿瘤。我们提出的研究将定义突变型和野生型 SAMD9L 在造血作用中的作用， 其结果将最终影响携带这些突变的患者的临床管理方式。不仅 该提案是否会显着增强我们对 SAMD9L 生物学的了解，但我们将广泛讨论如何 染色体非整倍性可能是对细胞应激的适应性反应，这可能是一种共享的 跨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.

儿科 MDS 和骨髓衰竭相关的 SAMD9 和 SAMD9L 种系突变会损害原代造血细胞的多种途径。

• 发表时间: 2021
• 影响因子: 11.4
• 作者: Thomas 3rd, Melvin E;Abdelhamed, Sherif;Hiltenbrand, Ryan;Schwartz, Jason R;Sakurada, Sadie Miki;Walsh, Michael;Song, Guangchun;Ma, Jing;Pruett;Klco, Jeffery M
• 通讯作者: Klco, Jeffery M

Functional characterization of cooperating MGA mutations in RUNX1::RUNX1T1 acute myeloid leukemia.

RUNX1::RUNX1T1 急性髓系白血病中协同 MGA 突变的功能特征。

• 发表时间: 2024-03-07
• 影响因子: 11.4
• 作者: Thomas 3rd, Melvin E;Qi, Wenqing;Walsh, Michael P;Ma, Jing;Westover, Tamara;Abdelhamed, Sherif;Ezzell, Lauren J;Rolle, Chandra;Xiong, Emily;Rosikiewicz, Wojciech;Xu, Beisi;Loughran, Allister J;Pruett;Janke, Laura J;Klco, Je
• 通讯作者: Klco, Je

The genomic landscape of pediatric myelodysplastic syndromes.

儿科骨髓增生异常综合征的基因组景观。

• 发表时间: 2017
• 影响因子: 16.6
• 作者: Schwartz, Jason R;Ma, Jing;Lamprecht, Tamara;Walsh, Michael;Wang, Shuoguo;Bryant, Victoria;Song, Guangchun;Wu, Gang;Easton, John;Kesserwan, Chimene;Nichols, Kim E;Mullighan, Charles G;Ribeiro, Raul C;Klco, Jeffery M
• 通讯作者: Klco, Jeffery M