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

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...

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Vydáno v:	Leukemia Ročník 35; číslo 11; s. 3232 - 3244
Hlavní autoři:	Thomas, Melvin E., Abdelhamed, Sherif, Hiltenbrand, Ryan, Schwartz, Jason R., Sakurada, Sadie Miki, Walsh, Michael, Song, Guangchun, Ma, Jing, Pruett-Miller, Shondra M., Klco, Jeffery M.
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 01.11.2021 Nature Publishing Group
Témata:	13 14/19 38/91 631/67/70 631/80/86 82 Animals Apoptosis Bone marrow Bone marrow cells Bone Marrow Failure Disorders - genetics Bone Marrow Failure Disorders - metabolism Bone Marrow Failure Disorders - pathology Cancer in children Cancer Research Cell cycle Cell proliferation Cells (biology) Cellular signal transduction Child Chromosome 7 Critical Care Medicine Development and progression DNA Damage DNA Repair Gene expression Gene mutations Genetic aspects Genetic Predisposition to Disease Germ-Line Mutation Health aspects Hematology Hematopoiesis Hematopoietic stem cells Hematopoietic Stem Cells - metabolism Hematopoietic Stem Cells - pathology Humans Intensive Internal Medicine Intracellular Signaling Peptides and Proteins - genetics Medicine Medicine & Public Health Mice Mice, Knockout Monosomy Mutation Myelodysplastic syndrome Myelodysplastic syndromes Myelodysplastic Syndromes - genetics Myelodysplastic Syndromes - metabolism Myelodysplastic Syndromes - pathology Oncology Pediatric research Pediatrics Progenitor cells Protein Biosynthesis Proteins Transcription Tumor Suppressor Proteins - genetics Tumor Suppressor Proteins - physiology United States
ISSN:	0887-6924, 1476-5551, 1476-5551
On-line přístup:	Získat plný text
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Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	0887-6924 1476-5551 1476-5551
DOI:	10.1038/s41375-021-01212-6