Polycomb repressive complexes as therapeutic targets in hematologic malignancies.

Polycomb-group proteins form PRC1 and PRC2 complexes that mediate heritable transcriptional repression via H2AK119 ubiquitination and H3K27 trimethylation. Canonical PRC1 catalyzes H2AK119 monoubiquitination through RING1A/B, whereas PRC2 deposits H3K27me3 via EZH1/2. Variant PRC1 (vPRC1) and PRC2 subtypes use distinct recruitment mechanisms, enabling both PRC2-dependent and -independent silencing. In hematopoiesis, components of PRC1, such as BMI1, and those of PRC1.1, including BCOR and PCGF1, have been well characterized for their roles in governing hematopoietic stem cell (HSC) self-renewal and lineage specification. Similarly, PRC2 components, particularly EZH1/2, SUZ12, and EED, are essential for the maintenance of HSCs. Aberrations in PRC1/2, such as gain- or loss-of-function mutations in EZH2 and loss-of-function mutations in BCOR, drive hematologic malignancies, including acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and lymphomas. In malignant lymphoma, mutations in chromatin regulators (e.g., EZH2, KMT2D, and CREBBP) reshape the epigenetic landscape, disrupting differentiation and immune recognition. Elevated H3K27me3 represents an early and shared epigenetic feature across diverse subclones in lymphoid neoplasms, including adult T-cell leukemia/lymphoma (ATL). Therapeutic targeting of H3K27me3 with EZH2-selective inhibitors such as tazemetostat has shown clinical benefit in lymphoma; however, their efficacy is limited by functional redundancy with EZH1. The dual EZH1/2 inhibitor valemetostat overcomes this limitation by reactivating tumor-suppressor genes, achieving durable responses in ATL and peripheral T-cell lymphoma (PTCL). Nonetheless, therapeutic resistance can emerge through PRC2 gatekeeper mutations and compensatory DNA methylation. These findings underscored the value of targeting the dysregulated epigenome and support the continued clinical development of dual EZH1/2 inhibitors.