Related Experiment Video
Updated: Nov 12, 2025
Use of Hematopoietic Stem Cell Transplantation to Assess the Origin of Myelodysplastic Syndrome
Published on: October 3, 2018
Pediatric MDS and bone marrow failure-associated germline mutations in SAMD9 and SAMD9L impair multiple pathways in
Melvin E Thomas1, Sherif Abdelhamed1, Ryan Hiltenbrand1
1Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.
Abstract:
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.
Insights
Germline mutations in SAMD9 and SAMD9L genes are linked to pediatric myelodysplastic syndromes (MDS). These mutations impair hematopoietic stem and progenitor cells (HSPCs), causing DNA damage and apoptosis, contributing to bone marrow failure.
Area of Science:
- Genetics and Molecular Biology
- Hematology
- Cell Biology
Background:
- Pediatric myelodysplastic syndromes (MDS) are a group of disorders characterized by ineffective blood cell production and bone marrow failure.
- Monosomy 7, a common chromosomal abnormality in pediatric MDS, is frequently associated with germline mutations in SAMD9 and SAMD9L.
Purpose of the Study:
- To investigate the functional impact of wild-type and mutant SAMD9 and SAMD9L in hematopoietic stem and progenitor cells (HSPCs).
- To elucidate the cellular mechanisms by which SAMD9/SAMD9L mutations contribute to the pathogenesis of pediatric MDS.
Main Methods:
- Lentiviral overexpression of wild-type and mutant SAMD9/SAMD9L in primary mouse and human HSPCs.
- Protein interactome analysis, transcriptional profiling, and functional assays.
- Assessment of cell cycle, proliferation, protein translation, DNA damage repair, and apoptosis.
Main Results:
- SAMD9 and SAMD9L are multifunctional proteins that significantly alter cell cycle, proliferation, and protein translation in HSPCs.
- Expression of SAMD9/SAMD9L and their mutations induces DNA damage repair defects and apoptosis in hematopoietic cells.
- These molecular and cellular alterations provide a mechanism for impaired hematopoiesis and bone marrow hypocellularity in pediatric MDS.
Conclusions:
- SAMD9 and SAMD9L play critical roles in maintaining hematopoietic function.
- Mutations in SAMD9/SAMD9L disrupt normal HSPC function, leading to DNA damage, apoptosis, and contributing to the development of pediatric MDS.
- This study offers novel insights into the molecular underpinnings of SAMD9/SAMD9L-associated pediatric MDS.
Related Concept Videos
01:22Bone Marrow Sampling and Transplants
The transplant begins with high doses of chemotherapy and radiation treatment, which aim to destroy...
01:21Lineage Commitment