Abstract 6168: Investigating the mechanism of oncogenesis of BCOR-CCNB3 fusion positive sarcomas

Abstract BCOR-CCNB3 sarcomas (BCS) are a subtype of small cell sarcomas that represent a recently recognized group of solid tumors identified by rearrangements of BCOR. Gene expression profiles of patient samples demonstrate a very similar profile to other BCOR rearranged solid tumors, such as BCOR-MAML3 fusion sarcomas, and CCSK with BCOR ITD. BCOR is a corepressor of the transcription factor BCL6 and is a critical member of the non-canonical polycomb repressive complex (PRC), PRC1.1, which mediates transcriptional repression through epigenetic modifications. In stem cells, PRC1.1 complexes are recruited to the chromatin through binding of KDM2B to nonmethylated CpG islands, catalyzing the ubiquitination of the histone H2A (at Lys119) via the RING-PCGF1 enzymatic core, leading to the repression of target genes. Through this process, the PCGF1-interacting PUFD region of BCOR is critical for the BCOR-PRC1.1 interaction. Despite this evolving understanding of the diagnostic profile of BCS, preclinical and mechanistic investigations of BCOR rearranged sarcomas have been limited due to the lack of models. Here, using two distinct BCS model systems, we investigated the mechanism of how BCOR-CCNB3 contributes to the oncogenesis of BCS. First, BCOR was knocked down in NBC-1, a patient-derived BCOR-CCNB3 cell line, and confirmed by western blotting and qRTPCR. Next, we created a vector transposon system to create isogenic cell lines expressing FLAG-tagged BCOR-CCNB3 or wild type BCOR. Interestingly, in NBC-1 cells, while the knockdown of the fusion gene did not lead to a statistically significant change in proliferation or survival, RNA-seq analysis identified that BCOR-CCNB3 knockdown led to a significant decrease of the expression of HOX family genes. Furthermore, co-IP identified that the fusion BCOR-CCNB3 was not bound to PRC1.1 components, including KDM2B, RING1, and PCGF1. In the isogenic cell model, we were able to establish an inducible BCOR-CCNB3 expression model, and demonstrate that the exogenous expression of BCOR-CCNB3 leads to increased cell proliferation.These results indicate that the BCOR-CCNB3 oncogenesis occurs through the disruption of the PRC1.1 complex function, and cannot be reversed by fusion gene targeting. Future work is currently ongoing to define the interaction of BCOR-CCNB3 with the various subunits of PRC1.1 through co-immunoprecipitations, IP-mass spectrometry and CUT&Tag analysis. Citation Format: Victoria Ann Pete, Ryota Shirai, Sydney Hakim, Joshua Broadman, Naoki Oike, Andrew E. Goodspeed, Masanori Hayashi. Investigating the mechanism of oncogenesis of BCOR-CCNB3 fusion positive sarcomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6168.