BCOR Internal Tandem Duplication Expression in Neural Stem Cells Promotes Growth, Invasion, and Expression of PRC2 Targets

• Published in: International journal of molecular sciences 2021-04, Vol.22 (8), p.3913
• Main Authors: Nakata, Satoshi, Yuan, Ming, Rubens, Jeffrey A, Kahlert, Ulf D, Maciaczyk, Jarek, Raabe, Eric H, Eberhart, Charles G
• Format: Article
• Language: English
• Subjects: Animals; Bcl-6 protein; BCOR; BCORL1; Cell Line, Tumor; Cell Proliferation - genetics; Central nervous system; Central Nervous System Neoplasms - genetics; Central Nervous System Neoplasms - pathology; Derepression; Differentiation (biology); embryonal tumor; Epigenetics; Gene deletion; Gene Duplication - genetics; Gene expression; Gene Expression Regulation, Neoplastic - genetics; Growth factors; Histones; Humans; Medical prognosis; Mice; Mutation; Neoplasm Invasiveness - genetics; Neoplasm Invasiveness - pathology; Neural stem cells; Neural Stem Cells - metabolism; Neural Stem Cells - pathology; Polycomb group proteins; polycomb repressive complex; Polycomb-Group Proteins - genetics; Polymerase chain reaction; Protein expression; Proteins; Proto-Oncogene Proteins - genetics; Repressor Proteins - genetics; Reproduction (copying); Stem cell transplantation; Stem cells; Tandem Repeat Sequences - genetics; Transcription; tumor model; Tumors
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22083913

Central nervous system tumor with BCL6-corepressor internal tandem duplication (CNS-BCOR ITD) is a malignant entity characterized by recurrent alterations in exon 15 encoding the essential binding domain for the polycomb repressive complex (PRC). In contrast to deletion or truncating mutations seen in other tumors, BCOR expression is upregulated in CNS-BCOR ITD, and a distinct oncogenic mechanism has been suggested. However, the effects of this change on the biology of neuroepithelial cells is poorly understood. In this study, we introduced either wildtype BCOR or BCOR-ITD into human and murine neural stem cells and analyzed them with quantitative RT-PCR and RNA-sequencing, as well as growth, clonogenicity, and invasion assays. In human cells, BCOR-ITD promoted derepression of PRC2-target genes compared to wildtype BCOR. A similar effect was found in clinical specimens from previous studies. However, no growth advantage was seen in the human neural stem cells expressing BCOR-ITD, and long-term models could not be established. In the murine cells, both wildtype BCOR and BCOR-ITD overexpression affected cellular differentiation and histone methylation, but only BCOR-ITD increased cellular growth, invasion, and migration. BCOR-ITD overexpression drives transcriptional changes, possibly due to altered PRC function, and contributes to the oncogenic transformation of neural precursors.