Extended Data Fig. 7: MEN1-M327I endogenous gene-editing induces drug resistance to different Menin-inhibitors in leukemia cell lines.
From: MEN1 mutations mediate clinical resistance to menin inhibition
a) Sanger-sequencing tracks showing gene-editing in MV4;11 and OCI-AML3 cells generating stable cell lines harboring the mutations indicated above the respective plots at the endogenous MEN1-locus. b) Dose-response curves of M327I homozygous or -WT MV4;11 cells to a high-dose range of revumenib. c) Dose-response curves of M327I heterozygous or -WT MV4;11 cells to MI-3454. d) Dose-response curves showing the sensitivity of OCI-AML3 (NPM1) cells harboring the MEN1-M327I mutation to revumenib, MI-3454 and the Daiichi-Sankyo compound. e) Dose-response curves showing the sensitivity of OCI-AML3 (NPM1) cells harboring the MEN1-T349M mutation to revumenib, MI-3454 and the Daiichi-Sankyo compound. f) Dose-response curves showing the sensitivity of MV4;11 cells harboring homozygous or heterozygous MEN1-M327I mutations to the covalent binder MI-89. g) Dose-response curves of S160C or -WT MV4;11 cells to revumenib. b—g) Cell counts were measured by flow cytometry and displayed relative to the DMSO control (mean +/− SEM, n = 4, each 3 technical replicates). h) Fluorescence-based cell competition assay measuring relative cell fitness of MV4;11-MEN1-WT, -M327I or -T349M mutant cells in the presence or absence of revumenib (100nM) over the course of 21 days by flow cytometry (N = 4, mean +/− SD). b–g) Statistical analysis was performed using an unpired t-test, two tailed, multiple comparisons. *** p < 0.001; **p < 0.01; *p < 0.05.
