Fig. 5: Aberrant enrichment of H3K4me3 in KMT2A fusion target gene bodies is sensitive to disruption of Menin localization.

a, The transcriptional scaffold protein Menin is enriched at fusion oncoprotein-binding sites in KMT2Ar cell lines. For all box plots, the center line indicates the median, box limits represent the first and third quartiles, and whiskers show all data within 1.5 times the IQR of the lower and upper quartiles; outliers are not shown. P values were computed using a two-sample t test (two sided). For each sample, n values are listed for wild-type sites and oncoprotein sites: SEM: n = 8,168, 91; RS4;11: n = 10,287, 92; KOPN-8: n = 9,723, 192. b, Cell survival curves for the SEM, RS4;11 and KOPN-8 cell lines in response to treatment with increasing concentrations of the Menin binding inhibitor VTP50469 (Menin-i) for 72 h. Error bars indicate the s.d. of three replicates. c, Same as in b except that treatment with VTP50469 was extended to 96 h. d, In response to treatment with 30 µM VTP50469 for 3 d, H3K4me3 is depleted at fusion oncoprotein-binding sites. n values are the same as in a. e, H3K4me3 peaks that show a significant loss of signal in response to treatment with VTP50469 are enriched in the gene bodies of oncoprotein target genes. f, Two examples of KMT2A–AF4-bound genes (TAPT1 and PAN3) in SEM cells that lose H3K4me3 in the gene body in response to treatment with 30 µM of the Menin inhibitor for 3 d. Black arrowheads point to annotated TSSs. Black scale bars, 10 kb. g, Heatmaps showing that Menin-sensitive H3K4me3 peaks located in the fusion oncoprotein target gene bodies of the indicated cell types are accessible and enriched for initiating RNA polymerase II, as indicated by RNAP2S5p CUTAC (Pol-CUTAC). Heatmaps are centered on Menin-sensitive H3K4me3 peaks falling in oncoprotein target gene bodies.