KDM2B is a histone demethylase that catalyzes removal of methyl groups from histone H3, primarily demethylating trimethylated H3 lysine-4 and dimethylated H3 lysine-36 12. Beyond its canonical demethylase activity, KDM2B functions in non-canonical PRC1.1 complex as a chr12-binding component regulating H2AK119 monoubiquitylation 34. KDM2B exhibits context-dependent transcriptional roles: it represses ribosomal RNA gene transcription 1, but independently of demethylase activity, it promotes IL-6 production through Brg1-mediated chr12 remodeling 5 and regulates metabolic enzyme expression in concert with MYC and ATF4 6. Pathogenic KDM2B variants cause neurodevelopmental disorder presenting with developmental delay, intellectual disability, autism, and congenital organ anomalies, with an identifiable epigenetic signature in peripheral blood 7. KDM2B hyperactivity associates with tumorigenesis; KDM2B fusions characterize soft tissue sarcomas within the BCOR-associated sarcoma family 8. In immune contexts, KDM2B regulates regulatory T cell plasticity and activation, and its deletion enhances anti-tumor immunity 4. KDM2B's demethylase activity can be inhibited by oncometabolite 2-hydroxyglutarate in IDH-mutant cancers, altering genome-wide methylation patterns 9.