title: Genomic instability in induced stem cells.
abstract: 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.
authors.affiliation: Department of Experimental Oncology, IFOM-IEO Campus, Istituto Europeo di Oncologia, Milan, Italy.
authors.forename: C E
authors.initials: CE
authors.lastname: Pasi
authors.forename: A
authors.initials: A
authors.lastname: Dereli-Öz
authors.forename: S
authors.initials: S
authors.lastname: Negrini
authors.forename: M
authors.initials: M
authors.lastname: Friedli
authors.forename: G
authors.initials: G
authors.lastname: Fragola
authors.forename: A
authors.initials: A
authors.lastname: Lombardo
authors.forename: G
authors.initials: G
authors.lastname: Van Houwe
authors.forename: L
authors.initials: L
authors.lastname: Naldini
authors.forename: S
authors.initials: S
authors.lastname: Casola
authors.forename: G
authors.initials: G
authors.lastname: Testa
authors.forename: D
authors.initials: D
authors.lastname: Trono
authors.forename: P G
authors.initials: PG
authors.lastname: Pelicci
authors.forename: T D
authors.initials: TD
authors.lastname: Halazonetis
mesh_terms: D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D048430:Cell Shape; D002478:Cells, Cultured; D055028:Comparative Genomic Hybridization; D004261:DNA Replication / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D051519:Fibroblast Growth Factor 4 / Q000378:metabolism; D042822:Genomic Instability; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000502:physiology* / Q000637:transplantation; D000090062:Kruppel-Like Factor 4; D008321:Mammary Glands, Animal / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D015689:Oncogene Protein p21(ras) / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D013312:Stress, Physiological
chemical_list: D004268:DNA-Binding Proteins; C474773:ERas protein, mouse; C496446:Fgf4 protein, mouse; D051519:Fibroblast Growth Factor 4; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; C489428:Myc protein, mouse; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D011993:Recombinant Fusion Proteins; C421709:zinc finger protein 296, mouse; D000469:Alkaline Phosphatase; D015689:Oncogene Protein p21(ras)