Human induced pluripotent stem cells (hiPSCs) are widely used for disease modelling and regenerative medicine, yet their utility depends on maintaining molecular integrity during long-term culture. BCOR (BCL6 Co-Repressor) mutations are among the most recurrent culture-acquired alterations in hiPSCs, but their functional consequences remain poorly understood. Here, we show that hiPSC BCOR mutations are predominantly truncating indels enriched in exon 7, defining a mutational landscape distinct from that observed in cancer. Multi-omics profiling reveals that BCOR loss drives widespread chromatin, transcriptomic and proteomic remodelling, with coordinated activation of developmental, pluripotency-associated and mitochondrial metabolism programmes. To facilitate routine surveillance, we develop a cost-effective TaqMan qPCR assay that accurately identifies BCOR-mutant hiPSCs across independent cell lines. Finally, we demonstrate that correction of BCOR mutation by CRISPR-Cas9 only partially restores the wildtype molecular state, highlighting the importance of early detection and monitoring of adaptive mutations in hiPSC cultures.
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