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Recurrent chromosomal imbalances provide selective advantage to human embryonic stem cells under enhanced replicative stress conditions.

Authors
  • Mus, Liselot M1, 2
  • Van Haver, Stéphane1, 2
  • Popovic, Mina3
  • Trypsteen, Wim1, 2
  • Lefever, Steve1, 2
  • Zeltner, Nadja4
  • Ogando, Yudelca5
  • Jacobs, Eva Z1
  • Denecker, Geertrui1, 2
  • Sanders, Ellen1, 2
  • Van Neste, Christophe1, 2
  • Vanhauwaert, Suzanne1, 2
  • Decaesteker, Bieke1, 2
  • Deforce, Dieter2, 6
  • Van Nieuwerburgh, Filip2, 6
  • Mestdagh, Pieter1, 2
  • Vandesompele, Jo1, 2
  • Menten, Björn1
  • De Preter, Katleen1, 2
  • Studer, Lorenz7, 8
  • And 4 more
  • 1 Department of Biomolecular Medicine, Ghent University, Ghent, Belgium. , (Belgium)
  • 2 Ghent University, Cancer Research Institute Ghent (CRIG), Ghent, Belgium. , (Belgium)
  • 3 Ghent-Fertility and Stem Cell Team (G-FaST), Department for Reproductive Medicine, Ghent University Hospital, Ghent, Belgium. , (Belgium)
  • 4 Center for Molecular Medicine, Department of Biochemistry & Molecular Biology and Department of Cellular Biology, University of Georgia, Athens, Georgia, USA. , (Georgia)
  • 5 Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, USA.
  • 6 Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium. , (Belgium)
  • 7 The Center for Stem Cell Biology, Sloan Kettering Institute, New York, USA.
  • 8 Developmental Biology Program, Sloan Kettering Institute, New York, USA.
Type
Published Article
Journal
Genes Chromosomes and Cancer
Publisher
Wiley (John Wiley & Sons)
Publication Date
Apr 01, 2021
Volume
60
Issue
4
Pages
272–281
Identifiers
DOI: 10.1002/gcc.22931
PMID: 33336840
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Human embryonic stem cells (hESCs) and embryonal tumors share a number of common features, including a compromised G1/S checkpoint. Consequently, these rapidly dividing hESCs and cancer cells undergo elevated levels of replicative stress, inducing genomic instability that drives chromosomal imbalances. In this context, it is of interest that long-term in vitro cultured hESCs exhibit a remarkable high incidence of segmental DNA copy number gains, some of which are also highly recurrent in certain malignancies such as 17q gain (17q+). The selective advantage of DNA copy number changes in these cells has been attributed to several underlying processes including enhanced proliferation. We hypothesized that these recurrent chromosomal imbalances become rapidly embedded in the cultured hESCs through a replicative stress driven Darwinian selection process. To this end, we compared the effect of hydroxyurea-induced replicative stress vs normal growth conditions in an equally mixed cell population of isogenic euploid and 17q + hESCs. We could show that 17q + hESCs rapidly overtook normal hESCs. Our data suggest that recurrent chromosomal segmental gains provide a proliferative advantage to hESCs under increased replicative stress, a process that may also explain the highly recurrent nature of certain imbalances in cancer. © 2020 Wiley Periodicals LLC.

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