TY - JOUR
T1 - Depletion of TP53 in Human Pluripotent Stem Cells Triggers Malignant-Like Behavior
AU - Montilla-Rojo, Joaquin
AU - Eleveld, Thomas F
AU - van Soest, Marnix
AU - Hillenius, Sanne
AU - Timmerman, Dennis M
AU - Gillis, Ad J M
AU - Roelen, Bernard A J
AU - Mummery, Christine L
AU - Looijenga, Leendert H J
AU - Salvatori, Daniela C F
N1 - © 2025 The Author(s). Advanced Biology published by Wiley‐VCH GmbH.
PY - 2025
Y1 - 2025
N2 - Human pluripotent stem cells (hPSCs) tend to acquire genetic aberrations upon culture in vitro. Common aberrations are mutations in the tumor suppressor TP53, suspected to confer a growth-advantage to the mutant cells. However, their full impact in the development of malignant features and safety of hPSCs for downstream applications is yet to be elucidated. Here, TP53 is knocked out in hPSCs using CRISPR-Cas9 and compared them with isogenic wild-type hPSCs and human germ cell tumor lines as models of malignancy. While no major changes in proliferation, pluripotency, and transcriptomic profiles are found, mutant lines display aberrations in some of the main chromosomal hotspots for genetic abnormalities in hPSCs. Additionally, enhanced clonogenic and anchorage-free growth, alongside resistance to chemotherapeutic compounds is observed. The results indicate that common TP53-depleting mutations in hPSCs, although potentially overlooked by standard analyses, can impact their behavior and safety in a clinical setting.
AB - Human pluripotent stem cells (hPSCs) tend to acquire genetic aberrations upon culture in vitro. Common aberrations are mutations in the tumor suppressor TP53, suspected to confer a growth-advantage to the mutant cells. However, their full impact in the development of malignant features and safety of hPSCs for downstream applications is yet to be elucidated. Here, TP53 is knocked out in hPSCs using CRISPR-Cas9 and compared them with isogenic wild-type hPSCs and human germ cell tumor lines as models of malignancy. While no major changes in proliferation, pluripotency, and transcriptomic profiles are found, mutant lines display aberrations in some of the main chromosomal hotspots for genetic abnormalities in hPSCs. Additionally, enhanced clonogenic and anchorage-free growth, alongside resistance to chemotherapeutic compounds is observed. The results indicate that common TP53-depleting mutations in hPSCs, although potentially overlooked by standard analyses, can impact their behavior and safety in a clinical setting.
KW - TP53
KW - genetic aberration
KW - human germ cell tumor
KW - human pluripotent stem cell
KW - malignancy
KW - pluripotency
UR - https://www.mendeley.com/catalogue/485c40e2-b3b4-3da0-9032-aff12ac658b5/
U2 - 10.1002/adbi.202400538
DO - 10.1002/adbi.202400538
M3 - Article
C2 - 39760438
SN - 2701-0198
SP - e2400538
JO - Advanced biology
JF - Advanced biology
ER -