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The PCGF Ub-like fold discriminator (PUFD) domain at the C-terminus of BCOR forms a heterodimer with PCGF1, serving as a critical interface for its polycomb-dependent functions. Internal tandem duplication (ITD) mutations in BCOR, causing in-frame duplications of 20 to 40 amino acids in the PUFD domain, are observed in heterogeneous tumors including sarcomas (kidney, bone, and endometrium) and neuroepithelial tumors in the brain. To dissect the molecular mechanisms underlying aberrant function of BCOR-ITD mutants, we employed mouse embryonic stem (mES) cells expressing either transgenic or endogenous BCOR-ITD. Our results indicate that the BCOR-ITD mutation does not disrupt the BCOR-PCGF1 interaction, instead maintaining the integrity of the vPRC1.1 complex. While displaying subtle changes in imprinted gene expression during differentiation toward a neural lineage, BCOR-ITD mutants also had no growth phenotype in culture. Furthermore, we found that CD24+ cells were enriched, as expected, during neural progenitor differentiation in both wildtype and mutant cells. However, sensitization of BCOR-ITD mES cells with EZH2 inhibitor during differentiation resulted in an unexpected enrichment of a CD24+CD26+ subpopulation, indicating aberrant cell fate that was also prevalent in a BCOR truncation mutant. Together, our results suggest that BCOR-ITD may largely retain wildtype function, but with increased susceptibility to synergistic stress on the Polycomb pathway.<\/jats:p>","DOI":"10.1093\/genetics\/iyaf133","type":"journal-article","created":{"date-parts":[[2025,7,12]],"date-time":"2025-07-12T04:47:41Z","timestamp":1752295661000},"source":"Crossref","is-referenced-by-count":1,"title":["Analysis of a BCOR internal tandem duplication in mouse embryonic stem cell to neuronal precursor differentiation"],"prefix":"10.1093","volume":"231","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0390-8140","authenticated-orcid":false,"given":"Zuzer","family":"Dhoondia","sequence":"first","affiliation":[{"name":"Division of Genetics, Department of Medicine, Brigham and Women's Hospital , Boston, MA 02215 ,","place":["United States"]},{"name":"Department of Genetics, Harvard Medical School, Harvard University , Boston, MA 02115 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyuckjoon","family":"Kang","sequence":"additional","affiliation":[{"name":"Division of Genetics, Department of Medicine, Brigham and Women's Hospital , Boston, MA 02215 ,","place":["United States"]},{"name":"Department of Genetics, Harvard Medical School, Harvard University , Boston, MA 02115 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kwangwoon","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Genetics, Department of Medicine, Brigham and Women's Hospital , Boston, MA 02215 ,","place":["United States"]},{"name":"Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Harvard University , Boston, MA 02115 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip A","family":"Cole","sequence":"additional","affiliation":[{"name":"Division of Genetics, Department of Medicine, Brigham and Women's Hospital , Boston, MA 02215 ,","place":["United States"]},{"name":"Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Harvard University , Boston, MA 02115 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitzi I","family":"Kuroda","sequence":"additional","affiliation":[{"name":"Division of Genetics, Department of Medicine, Brigham and Women's Hospital , Boston, MA 02215 ,","place":["United States"]},{"name":"Department of Genetics, Harvard Medical School, Harvard University , Boston, MA 02115 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,7,12]]},"reference":[{"key":"2025090305271843100_iyaf133-B1","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1038\/s41586-024-07487-w","article-title":"Accurate structure prediction of biomolecular interactions with AlphaFold 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