Chemogenomic dissection of the role of Class I Histone Deacetylases as therapeutically relevant dependencies in H3K27M-glioma

Disease pathogenesis is driven by epigenetic dysregulation which can be exploited using histone deacetylase (HDAC) inhibitors. However, the precise mechanism of efficacy for these agents in DMG has not been fully explored, and their translational potential has been limited by off-target effects and poor central nervous system (CNS) penetration of clinically available drugs.

We here confirm genetic and chemical dependencies of nuclear-localized HDAC class I isoforms, particularly HDAC2, in patient-derived DMG cell lines using CRISPR/Cas9 screening and chemical validation. Moreover, we identify an HDAC inhibitor termed “Compound 26” with HDAC1/2 isoform selectivity and excellent CNS penetration. Using RNA-sequencing and HiChIP, we show that Compound 26 induces immediate transcriptional rewiring of DMG cells to restore physiologic pontine histone marks and induce cell cycle arrest.