Abstract B49: Modeling a pathogenic SAMD9 mutation in human induced pluripotent stem cells
| Autor: | Jeffery M. Klco, Jon P. Connelly, Shondra M. Pruett-Miller, Jason R. Schwartz |
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| Rok vydání: | 2020 |
| Předmět: | |
| Zdroj: | Cancer Research. 80:B49-B49 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/1538-7445.pedca19-b49 |
| Popis: | Germline mutations in SAMD9 are the molecular determinants of some pedigrees with familial monosomy 7 and myelodysplastic syndrome (MDS) (OMIM 252270), MIRAGE syndrome (myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, enteropathy), and other nonsyndromic pediatric MDS. Mutations identified thus far have been associated with decreased growth of hematopoietic stem and progenitor cells (HSPCs) and bone marrow hypocellularity. Previous studies suggest that the wild-type function of SAMD9 is growth restrictive; therefore, the mutations identified in pediatric MDS have been deemed gain-of-function (GoF), given the exaggerated antiproliferative phenotype demonstrated in overexpression systems within nonhematopoietic cell lines, most commonly HEK-293T. To date, no model systems are available to study the impact of these mutations in their endogenous locus, a locus known to be induced by inflammatory stimuli, namely interferon (IFN). Here we report our development, using CRISPR/Cas9 genomic engineering, of two separate isogenic human induced pluripotent stem cell (iPSC) lines, derived from a non-neoplastic iPSC line (BJFF.6), containing a known pathogenic SAMD9 mutation (c.3406G>C; p.E1136Q), which we previously identified in a family with monosomy 7 and MDS. From this mutated iPSC line we are able to successfully differentiate hematopoietic precursors and myeloid cells that contain a pathogenic SAMD9 mutation. Using our novel pediatric MDS model system, we demonstrate that in the presence of IFN, viability of HSPCs (CD34+) and differentiated myeloid cells (CD13+) is significantly decreased when the SAMD9 p.E1136Q mutation is present (CD34+; WT=16.7% vs Mut=11.5% (p=0.05), CD13+; WT=22.6% vs. Mut=3.5% (p Citation Format: Jason R. Schwartz, Jon P. Connelly, Shondra M. Pruett-Miller, Jeffery M. Klco. Modeling a pathogenic SAMD9 mutation in human induced pluripotent stem cells [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr B49. |
| Databáze: | OpenAIRE |
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