BCOR x PCGF1

BCOR (BCL-6 corepressor) rearranged small round cell sarcoma (BRS) represents an uncommon soft tissue malignancy, frequently characterized by the BCOR::CCNB3 fusion. Other noteworthy fusions include BCOR::MAML3, BCOR::CLGN, BCOR::MAML1, ZC3H7B::BCOR, KMT2D::BCOR, CIITA::BCOR, RTL9::BCOR, and AHR::BCOR. The BCOR gene plays a pivotal role in the Polycomb Repressive Complex 1 (PRC1), essential for histone modification and gene silencing. It interfaces with the Polycomb group RING finger homolog (PCGF1). This study employed comprehensive in silico methodologies to investigate the structural and functional effects of BCOR fusion events in BRS. The analysis revealed significant alterations in the domain architecture of BCOR, which resulted in the loss of BCL6-regulated transcriptional repression. Furthermore, IUPred3 prediction indicated a significant increase in disorder in the C-terminal regions of the BCOR in the fusion proteins. A detailed analysis of the physicochemical properties by ProtParam revealed a decrease in isoelectric point, stability, and hydrophobicity. The analysis of protein structures predicted by AlphaFold3 using the PRODIGY algorithm revealed statistically significant deviations in binding affinities for BCOR-PCGF1 dimers and a non-canonical PRC1 variant tetramer compared to the wild-type BCOR. The findings provide a comprehensive summary and elucidation of the fusion proteome associated with BRS, suggesting a substantial impact on the stability and functionality of the fusion proteins, thereby contributing to the oncogenic mechanisms underlying BRS. In this study, we provide the first compilation and comparative analysis of the known BCOR fusions of BRS and introduce a new in silico approach to enhance a better understanding of the molecular basis of BRS.

Menin inhibitors that disrupt the menin-MLL interaction hold promise for treating specific acute myeloid leukemia (AML) subtypes, including those with KMT2A rearrangements (KMT2A-r), yet resistance remains a challenge. Here, through systematic chromatin-focused CRISPR screens, along with genetic, epigenetic, and pharmacologic studies in a variety of human and mouse KMT2A-r AML models, we uncovered a potential resistance mechanism independent of canonical menin-MLL targets. We show that a group of noncanonical menin targets, which are bivalently cooccupied by active menin and repressive H2AK119ub marks, are typically downregulated after menin inhibition. Loss of polycomb repressive complex 1.1 (PRC1.1) subunits, such as polycomb group ring finger 1 (PCGF1) or BCL6 corepressor (BCOR), leads to menin inhibitor resistance by epigenetic reactivation of these noncanonical targets, including MYC. Genetic and pharmacological inhibition of MYC can resensitize PRC1.1-deficient leukemia cells to menin inhibition. Moreover, we demonstrate that leukemia cells with the loss of PRC1.1 subunits exhibit reduced monocytic gene signatures and are susceptible to BCL2 inhibition, and that combinational treatment with venetoclax overcomes the resistance to menin inhibition in PRC1.1-deficient leukemia cells. These findings highlight the important roles of PRC1.1 and its regulated noncanonical menin targets in modulating the menin inhibitor response and provide potential strategies to treat leukemia with compromised PRC1.1 function.

Polycomb repressive complex (PRC) 1 regulates stem cell fate by mediating mono-ubiquitination of histone H2A at lysine 119. While canonical PRC1 is critical for hematopoietic stem and progenitor cell (HSPC) maintenance, the role of non-canonical PRC1 in hematopoiesis remains elusive. PRC1.1, a non-canonical PRC1, consists of PCGF1, RING1B, KDM2B, and BCOR. We recently showed that PRC1.1 insufficiency induced by the loss of PCGF1 or BCOR causes myeloid-biased hematopoiesis and promotes transformation of hematopoietic cells in mice. Here we show that PRC1.1 serves as an epigenetic switch that coordinates homeostatic and emergency hematopoiesis. PRC1.1 maintains balanced output of steady-state hematopoiesis by restricting C/EBPα-dependent precocious myeloid differentiation of HSPCs and the HOXA9- and β-catenin-driven self-renewing network in myeloid progenitors. Upon regeneration, PRC1.1 is transiently inhibited to facilitate formation of granulocyte-macrophage progenitor (GMP) clusters, thereby promoting emergency myelopoiesis. Moreover, constitutive inactivation of PRC1.1 results in unchecked expansion of GMPs and eventual transformation. Collectively, our results define PRC1.1 as a novel critical regulator of emergency myelopoiesis, dysregulation of which leads to myeloid transformation.