Pediatric MDS and bone marrow failure-associated germline mutations in SAMD9 and SAMD9L impair multiple pathways in primary hematopoietic cells.
Pediatric MDS and bone marrow failure-associated germline mutations in SAMD9 and SAMD9L impair multiple pathways in primary hematopoietic cells.
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DOI：
10.1038/s41375-021-01212-6
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发表时间：
2021-11
期刊：
影响因子：
11.4
通讯作者：
Klco JM
中科院分区：
文献类型：
--
作者：
Thomas ME 3rd;Abdelhamed S;Hiltenbrand R;Schwartz JR;Sakurada SM;Walsh M;Song G;Ma J;Pruett-Miller SM;Klco JM
小儿骨髓增生异常综合征（MDS）是一种异质性疾病，与造血功能受损、骨髓细胞减少相关，并经常伴有涉及7号染色体（7号单体）的缺失。我们和其他人最近在7号单体和MDS儿童中发现了SAMD9和SAMD9L的杂合种系突变。我们先前证明了这些基因产物在非造血细胞中的抗增殖作用，其患者相关突变加剧了这种作用。在这里，我们使用慢病毒过表达方法来评估野生型和突变型SAMD9或SAMD9L在原代小鼠或人造血干细胞和祖细胞（HSPC）中的功能影响和潜在的细胞过程。使用蛋白质相互作用组分析，转录谱分析和功能验证的组合，我们表明，SAMD9和SAMD9L是多功能的蛋白质，导致细胞周期，细胞增殖和蛋白质翻译的HSPC中的深刻改变。重要的是，我们的分子和功能研究还表明，这些基因的表达及其突变导致细胞环境，促进DNA损伤修复缺陷，并最终在造血细胞凋亡。这项研究为SAMD9和SAMD9L提供了新的功能见解，以及它们的突变如何可能改变造血功能并导致骨髓细胞减少（儿科MDS的标志）。
Pediatric myelodysplastic syndromes (MDS) are a heterogeneous disease group associated with impaired hematopoiesis, bone marrow hypocellularity, and frequently have deletions involving chromosome 7 (monosomy 7). We and others recently identified heterozygous germline mutations in SAMD9 and SAMD9L in children with monosomy 7 and MDS. We previously demonstrated an antiproliferative effect of these gene products in non-hematopoietic cells, which was exacerbated by their patient-associated mutations. Here, we used a lentiviral overexpression approach to assess the functional impact and underlying cellular processes of wild-type and mutant SAMD9 or SAMD9L in primary mouse or human hematopoietic stem and progenitor cells (HSPC). Using a combination of protein interactome analyses, transcriptional profiling, and functional validation, we show that SAMD9 and SAMD9L are multifunctional proteins that cause profound alterations in cell cycle, cell proliferation, and protein translation in HSPCs. Importantly, our molecular and functional studies also demonstrated that expression of these genes and their mutations leads to a cellular environment that promotes DNA damage repair defects and ultimately apoptosis in hematopoietic cells. This study provides novel functional insights into SAMD9 and SAMD9L and how their mutations can potentially alter hematopoietic function and lead to bone marrow hypocellularity, a hallmark of pediatric MDS.
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影响因子：
4.4
作者：
Li CF;MacDonald JR;Wei RY;Ray J;Lau K;Kandel C;Koffman R;Bell S;Scherer SW;Alman BA
通讯作者：
Alman BA
影响因子：
16.6
作者：
Alvarez S;Díaz M;Flach J;Rodriguez-Acebes S;López-Contreras AJ;Martínez D;Cañamero M;Fernández-Capetillo O;Isern J;Passegué E;Méndez J
通讯作者：
Méndez J
DOI：
10.1172/jci91913
发表时间：
2017-05-01
期刊：
The Journal of clinical investigation
影响因子：
--
作者：
Buonocore F;Kühnen P;Suntharalingham JP;Del Valle I;Digweed M;Stachelscheid H;Khajavi N;Didi M;Brady AF;Blankenstein O;Procter AM;Dimitri P;Wales JKH;Ghirri P;Knöbl D;Strahm B;Erlacher M;Wlodarski MW;Chen W;Kokai GK;Anderson G;Morrogh D;Moulding DA;McKee SA;Niemeyer CM;Grüters A;Achermann JC
通讯作者：
Achermann JC
一对旁系同源哺乳动物宿主限制因子形成对抗痘病毒感染的关键宿主屏障
影响因子：
6.7
作者：
Meng X;Zhang F;Yan B;Si C;Honda H;Nagamachi A;Sun LZ;Xiang Y
通讯作者：
Xiang Y
影响因子：
3.6
作者：
Niemeyer, Charlotte M.;Baumann, Irith
通讯作者：
Baumann, Irith