title: Aneuploidy induces profound changes in gene expression, proliferation and tumorigenicity of human pluripotent stem cells.
abstract: Human pluripotent stem cells (hPSCs) tend to acquire genomic aberrations in culture, the most common of which is trisomy of chromosome 12. Here we dissect the cellular and molecular implications of this trisomy in hPSCs. Global gene expression analyses reveal that trisomy 12 profoundly affects the gene expression profile of hPSCs, inducing a transcriptional programme similar to that of germ cell tumours. Comparison of proliferation, differentiation and apoptosis between diploid and aneuploid hPSCs shows that trisomy 12 significantly increases the proliferation rate of hPSCs, mainly as a consequence of increased replication. Furthermore, trisomy 12 increases the tumorigenicity of hPSCs in vivo, inducing transcriptionally distinct teratomas from which pluripotent cells can be recovered. Last, a chemical screen of 89 anticancer drugs discovers that trisomy 12 raises the sensitivity of hPSCs to several replication inhibitors. Together, these findings demonstrate the extensive effect of trisomy 12 and highlight its perils for successful hPSC applications.
authors.affiliation: 1] Stem Cell Unit, Department of Genetics, Silberman Institute of Life Sciences, Hebrew University, Jerusalem 91904, Israel [2] Cancer Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
authors.forename: Uri
authors.initials: U
authors.lastname: Ben-David
authors.affiliation: Stem Cell Unit, Department of Genetics, Silberman Institute of Life Sciences, Hebrew University, Jerusalem 91904, Israel.
authors.forename: Gal
authors.initials: G
authors.lastname: Arad
authors.affiliation: Stem Cell Unit, Department of Genetics, Silberman Institute of Life Sciences, Hebrew University, Jerusalem 91904, Israel.
authors.forename: Uri
authors.initials: U
authors.lastname: Weissbein
authors.affiliation: Department of Biomedical Sciences and Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.
authors.forename: Berhan
authors.initials: B
authors.lastname: Mandefro
authors.affiliation: Stem Cell Unit, Department of Genetics, Silberman Institute of Life Sciences, Hebrew University, Jerusalem 91904, Israel.
authors.forename: Adva
authors.initials: A
authors.lastname: Maimon
authors.affiliation: Stem Cell Unit, Department of Genetics, Silberman Institute of Life Sciences, Hebrew University, Jerusalem 91904, Israel.
authors.forename: Tamar
authors.initials: T
authors.lastname: Golan-Lev
authors.affiliation: Department of Biomedical Sciences and Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.
authors.forename: Kavita
authors.initials: K
authors.lastname: Narwani
authors.affiliation: 1] Department of Molecular, Cell, and Developmental Biology, University of California-Los Angeles, Los Angeles, California 90095, USA [2] Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California-Los Angeles, Los Angeles, California 90095, USA.
authors.forename: Amander T
authors.initials: AT
authors.lastname: Clark
authors.affiliation: Centre for Stem Cell Biology, Department of Biomedical Science, University of Sheffield, Sheffield S10 2TN, UK.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Andrews
authors.affiliation: Stem Cell Unit, Department of Genetics, Silberman Institute of Life Sciences, Hebrew University, Jerusalem 91904, Israel.
authors.forename: Nissim
authors.initials: N
authors.lastname: Benvenisty
authors.affiliation: 1] Department of Biomedical Sciences and Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA [2] Zilkha Neurogenetic Institute, Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.
authors.forename: Juan
authors.initials: J
authors.lastname: Carlos Biancotti
mesh_terms: D000782:Aneuploidy; D063646:Carcinogenesis / Q000235:genetics*; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics*; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics*; D054278:Embryonal Carcinoma Stem Cells / Q000378:metabolism; D015870:Gene Expression / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D066298:In Vitro Techniques; D009369:Neoplasms / Q000235:genetics*; D009373:Neoplasms, Germ Cell and Embryonal / Q000235:genetics; D039904:Pluripotent Stem Cells / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism*; D018243:Teratocarcinoma / Q000235:genetics; D013724:Teratoma / Q000235:genetics; D014314:Trisomy / Q000235:genetics*
chemical_list: D012333:RNA, Messenger