Genomic instability in induced stem cells

Article Article scientifique Article Genomic instability in induced stem cells eng 2011-02-11 2011-02-11 author Pasi C. E. author Dereli-Öz A. author Negrini Simona 540829 author Friedli Marc 134865 author Fragola G. author Lombardo A. 0000-0001-8262-042X author Van Houwe Griet 410315 author Naldini Léo Georges Santi 0000-0002-7835-527X 413341 author Casola S. 0000-0001-5580-0986 author Testa G. 0000-0002-9104-0918 author Trono Didier 116006 author Pelicci P. G. 0000-0002-5076-2316 author Halazonetis Thanos 0000-0001-8384-5030 641033 Département de biologie moléculaire et cellulaire (MOCEL) 745-753 10.1038/cdd.2011.9 21311564 1350-9047 PMC3079512 https://www.nature.com/articles/cdd20119 <p>The ability to reprogram adult cells into stem cells has raised hopes for novel therapies for many human diseases. Typical stem cell reprogramming protocols involve expression of a small number of genes in differentiated somatic cells with the c-Myc and Klf4 proto-oncogenes typically included in this mix. We have previously shown that expression of oncogenes leads to DNA replication stress and genomic instability, explaining the high frequency of p53 mutations in human cancers. Consequently, we wondered whether stem cell reprogramming also leads to genomic instability. To test this hypothesis, we examined stem cells induced by a variety of protocols. The first protocol, developed specifically for this study, reprogrammed primary mouse mammary cells into mammary stem cells by expressing c-Myc. Two other previously established protocols reprogrammed mouse embryo fibroblasts into induced pluripotent stem cells by expressing either three genes, Oct4, Sox2 and Klf4, or four genes, OSK plus c-Myc. Comparative genomic hybridization analysis of stem cells derived by these protocols revealed the presence of genomic deletions and amplifications, whose signature was suggestive of oncogene-induced DNA replication stress. The genomic aberrations were to a significant degree dependent on c-Myc expression and their presence could explain why p53 inactivation facilitates stem cell reprogramming.</p> Dewey 540 Dewey 570 NCI NIH HHS R01 CA118827-04 Telethon TGT 39 Département de biochimie 144 43 Département de biologie moléculaire 161 false Cell death and differentiation 18 5 946201d3-02e0-4c29-9422-1221c5fa4b08 Article (Published version) Restricted Article-scientifique-from-crossref.pdf 2345622 application/pdf e4bb806087b342b6fdb6c808fe91cfe31f24642c1a1f7e993a08b961b8d741bf restrictedAccess Faculté des sciences / Section de chimie et biochimie / Département de biochimie Faculté des sciences / Section de biologie / Département de biologie moléculaire

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Negrini, Simona