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

Satoshi Nakata,Ulf D Kahlert,Ming Yuan,Eric H Raabe,Jarek Maciaczyk,Charles G Eberhart,Jeffrey A Rubens

doi:10.3390/ijms22083913

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.

Highlights

Central nervous system (CNS) tumor with B-cell lymphoma 6 protein (BCL6)-corepressor internal tandem duplication (CNS-BCOR ITD) is a malignant entity initially identified by Sturm et al [1], and more recently proposed as a distinct CNS tumor type by the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy [2,3]
The median overall survival time for CNS-BCOR ITD calculated by the Kaplan–Meier to PRC2-targets or associated with the H3K27me3 mark (Figure 2a and Supplementary Table S2) (GSEA with family-wise error rate (FWER), p value ≤ 0.01)
We found that BCOR-ITD expression results in derepression of PRC2 target genes in CNS tumors

Summary

Introduction

Central nervous system (CNS) tumor with BCL6-corepressor internal tandem duplication (CNS-BCOR ITD) is a malignant entity initially identified by Sturm et al [1], and more recently proposed as a distinct CNS tumor type by the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT) [2,3]. BCOR was originally identified as an interacting corepressor of B-cell lymphoma 6 protein (BCL6), and recent studies have revealed a genome-wide transcriptional impact via interactions with polycomb repressive complex 1.1 (PRC 1.1) [19]. Germline loss of BCOR induces oculo-facio-cardio-dental syndrome (OFCD) [22], which is inherited in an X-linked dominant mode and is lethal in males

Methods

Results

Conclusion