TY - JOUR
T1 - Aneuploidy induces profound changes in gene expression, proliferation and tumorigenicity of human pluripotent stem cells
AU - Ben-David, Uri
AU - Arad, Gal
AU - Weissbein, Uri
AU - Mandefro, Berhan
AU - Maimon, Adva
AU - Golan-Lev, Tamar
AU - Narwani, Kavita
AU - Clark, Amander T.
AU - Andrews, Peter W.
AU - Benvenisty, Nissim
AU - Carlos Biancotti, Juan
N1 - Publisher Copyright:
© 2014 Macmillan Publishers Limited.
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84911442522&partnerID=8YFLogxK
U2 - 10.1038/ncomms5825
DO - 10.1038/ncomms5825
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C2 - 25198699
AN - SCOPUS:84911442522
SN - 2041-1723
VL - 5
JO - Nature Communications
JF - Nature Communications
M1 - 4825
ER -