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

Abstract

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.

BCOR expression in paediatric pineoblastoma

“…In the same study, an elevated expression of BCOR at the RNA level was also detected in a CNS high grade neuroepithelial tumour with MN1 alteration (HGNET-MN1), but not in 8 other types of CNS tumours investigated. Overall, low expression of BCOR was observed so far in high grade gliomas (HGGs) of different molecular types, medulloblastomas, ependymomas, CNS neuroblastoma with FOXR2 activation (NBFOXR2), CNS Ewing sarcoma family tumour with CIC alteration (EFTCIC), atypical teratoid rhabdoid tumours (ATRTs), embryonal tumour with multilayered rosettes and choroid plexus carcinomas (CPCs) [16,17,20]. The evidence of BCOR nuclear expression detected by immunohistochemistry in HGNET-BCOR Joanna Trubicka, Maria Łastowska, Agnieszka Karkucińska-Więckowska, Magdalena Niemira, Maria Ejmont, Agnieszka Sowińska, Maciej Pronicki, Ewa Matyja, Wiesława Grajkowska tumours was presented in several recent studies [2,6,7,16], therefore indicating a potential diagnostic usefulness of this marker.…”