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Nat Commun. 2014 Sep 8;5:4825. doi: 10.1038/ncomms5825.

Aneuploidy induces profound changes in gene expression, proliferation and tumorigenicity of human pluripotent stem cells.

Author information

1
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.
2
Stem Cell Unit, Department of Genetics, Silberman Institute of Life Sciences, Hebrew University, Jerusalem 91904, Israel.
3
Department of Biomedical Sciences and Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.
4
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.
5
Centre for Stem Cell Biology, Department of Biomedical Science, University of Sheffield, Sheffield S10 2TN, UK.
6
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.

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.

PMID:
25198699
DOI:
10.1038/ncomms5825
[Indexed for MEDLINE]

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