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Pediatric MDS-Associated Germline Mutations in SAMD9 and SAMD9L Impair Multiple Pathways in Primary Hematopoietic Cells

ABSTRACT: Pediatric MDS-Associated Germline Mutations in SAMD9 and SAMD9L Impair Multiple Pathways in Primary Hematopoietic Cells

PROVIDER: PRJNA639279 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12007938_1.fastq.gz	Fastqsanger.gz
	SRR12007938_2.fastq.gz	Fastqsanger.gz
	SRR12007939_1.fastq.gz	Fastqsanger.gz
	SRR12007939_2.fastq.gz	Fastqsanger.gz
	SRR12007940_1.fastq.gz	Fastqsanger.gz

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Pediatric MDS-Associated Germline Mutations in SAMD9 and SAMD9L Impair Multiple Pathways in Primary Hematopoietic Cells

Project description:Here, we used a lentiviral over-expression 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 found that SAMD9 and SAMD9L are multifunctional proteins that cause profound alterations in cell cycle, protein translation, and proliferation of HSPCs. Importantly, our molecular and functional studies also demonstrated that expression of these genes and their mutations leads to a toxic cellular environment that promotes DNA-damage repair defects and ultimately lead to 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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Identification of SAMD9 and SAMD9L interactome in HEK293T cells

Project description:Recently, heterozygous germline mutations were identified in sterile alpha motif (SAM) domain-9 (SAMD9) and its paralog, SAMD9-like (SAMD9L) in children with monosomy 7 mediated MDS. Expression of SAMD9 and SAMD9L is induced by interferons and other inflammatory stimuli and causes reduced cell division and cell growth and most pathogenic mutations found in patients dramatically enhance these effects. The goal of this project is to identify the interactome of SAMD9 and SAMD9L to better understand their role in cell cycle and proliferation regulation

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

Project description: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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Project description:SAMD9 and SAMD9L (SAMD9/9L) are antiviral factors and myeloid tumor suppressors. They are critical for innate immune defense against several viruses, particularly the poxviruses. SAMD9/9L mutations with a gain-of-function (GoF) in inhibiting cell growth cause multisystem developmental disorders including many pediatric myelodysplastic syndromes. Predicted to be multi-domain proteins with an architecture like that of the NOD-like receptors, SAMD9/9L molecular functions and domain structures are largely unknown. Here, we identified a SAMD9/9L effector domain that functions by binding to double-stranded nucleic acids (dsNA) and determined the crystal structure of the domain in complex with DNA. Aided with precise mutations that differentially perturb dsNA binding, we demonstrated that the antiviral and antiproliferative functions of the wild-type and GoF SAMD9/9L variants rely on dsNA binding by the effector domain. Furthermore, we showed that GoF variants inhibit global protein synthesis, reduce translation elongation, and induce proteotoxic stress response, which all require dsNA binding by the effector domain. The identification of the structure and function of a SAMD9/9L effector domain provides a therapeutic target for SAMD9/9L associated human diseases.

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Human SAMD9 is a Virus-Activatable Anticodon Nuclease Inhibiting Codon-Specific Protein Synthesis

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