a, Global H3K27 acetylation density of Suz12.1842-expressing resistant MLL–AF9;NrasG12D leukaemia cells under long term (LT) treatment with 50 nM JQ1 (red bar), after 4 days of drug withdrawal (orange bar) and in Ren.713 controls (blue bar; statistical significance determined using Student’s t-test). b, Left panel, sorted fold change (FC) ratios of H3K27ac peaks in long-term JQ1-treated MLL–AF9;NrasG12D leukaemia cells expressing Suz12.1842 compared to cells expressing Ren.713 control shRNA. Included were all peaks showing > 10 reads per million in at least one condition. Right panel, top 15 gained peaks and their associated genes (defined using the closest transcription start site, TSS). The Myc proximal enhancer in the first intron of Pvt1 is highlighted in red as one of the most differentially enriched peaks (FC = 4.18). c, qRT–PCR validation of presented H3K27ac ChIP-seq at the indicated regions downstream of the Myc locus (n = 3, mean ± s.e.m., statistical significance determined using Student’s t-test). d, Gene set enrichment analysis plots of three publicly available gene sets associated with signalling pathways comparing expression changes in resistant MLL–AF9;NrasG12D AML cells induced by suppression of PRC2 complex members, compared to control cells expressing Ren.713 shRNA (n = 2) or empty vector (continuation of Fig. 2e, f). e, Core signature genes of KEGG-curated Wnt and TGF-β gene sets with increased expression in resistant murine MLL–AF9;NrasG12D cells, compared to sensitive cells. Red coloured bars indicate association with H3K27 methylation in JQ1-sensitive MLL–AF9;NrasG12D AML cells. f, H3K27 methylation density at three exemplified genes with high expression changes in JQ1-resistant murine AML.