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

Uri Ben-David, Gal Arad, Uri Weissbein, Berhan Mandefro, Adva Maimon, Tamar Golan-Lev, Kavita Narwani, Amander T. Clark, Peter W. Andrews, Nissim Benvenisty () and Juan Carlos Biancotti
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Uri Ben-David: Stem Cell Unit, Silberman Institute of Life Sciences, Hebrew University
Gal Arad: Stem Cell Unit, Silberman Institute of Life Sciences, Hebrew University
Uri Weissbein: Stem Cell Unit, Silberman Institute of Life Sciences, Hebrew University
Berhan Mandefro: Cedars-Sinai Medical Center
Adva Maimon: Stem Cell Unit, Silberman Institute of Life Sciences, Hebrew University
Tamar Golan-Lev: Stem Cell Unit, Silberman Institute of Life Sciences, Hebrew University
Kavita Narwani: Cedars-Sinai Medical Center
Amander T. Clark: Cell, and Developmental Biology, University of California-Los Angeles
Peter W. Andrews: Centre for Stem Cell Biology, University of Sheffield
Nissim Benvenisty: Stem Cell Unit, Silberman Institute of Life Sciences, Hebrew University
Juan Carlos Biancotti: Cedars-Sinai Medical Center

Nature Communications, 2014, vol. 5, issue 1, 1-11

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms5825

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