Figure 1.
Effect of combinatorial treatment with menin and FLT3 inhibitors in leukemia cells. (A-B) Growth inhibition in MOLM13 (expressing MLL-AF9 and FLT3-ITD) (A) and MV4;11 cells (expressing MLL-AF4 and FLT3-ITD) (B) treated with MI-3454, gilteritinib (Gilt), or their combination. (C) Flow cytometric analysis of apoptosis (annexin V+ cells) induced after 8 days of treatment of MOLM13 and MV4;11 cells with MI-3454, Gilt, or their combination. (D) Flow cytometric quantification of differentiation markers (CD11b+ and CD14+) in MV4;11 cells after single-agent or combinatorial treatment with MI-3454 and Gilt. (E) Gene expression studies in MV4;11 cells after 8 days of treatment with MI-3454, Gilt, or their combination. (A-E) Graphs are representative of 2 independent experiments performed in triplicate. (F-H) Comparison of differentially expressed (DE) genes (adjusted P < .05; fold change >|1.5|) from RNA sequencing (RNA-seq) studies in MOLM13 cells after 8 days of treatment with dimethyl sulfoxide (DMSO), MI-3454, Gilt, or their combination (n = 3 samples per treatment group). (F) Venn diagrams show the overlap of upregulated DE genes (right) and downregulated DE genes (left) relative to DMSO. (G) Heatmap of DE genes after k-means clustering of DE genes using a priori–determined 5 clusters. (H) Average z scores for all treatment groups calculated within each k-means cluster. (I) Summary of fast gene set enrichment analysis results for gene sets relating to targets of MYC, differentiation, or stemness from the RNA-seq studies in MOLM13. Each bubble represents a gene set. Size of bubbles on the plot indicates the level of significance, and y-axis indicates the normalized enrichment score (NES) for the gene sets. (J) Representative gene set enrichment plots for MYC targets for each treatment condition relative to DMSO for the Bild_Myc_Oncogenic_Signature gene set from MSigDB. The heatmaps show genes comprising the leading edge of the gene set enrichment plots. Red indicates high expression; blue indicates low expression; black arrows indicate MYC. *P < .05, **P < .01, ***P < .001, ****P < .0001 by 2- (A-B) or 1-way (C-E) analysis of variance with Tukey multiple comparison test. adj, adjusted; ES, enrichment score.

Effect of combinatorial treatment with menin and FLT3 inhibitors in leukemia cells. (A-B) Growth inhibition in MOLM13 (expressing MLL-AF9 and FLT3-ITD) (A) and MV4;11 cells (expressing MLL-AF4 and FLT3-ITD) (B) treated with MI-3454, gilteritinib (Gilt), or their combination. (C) Flow cytometric analysis of apoptosis (annexin V+ cells) induced after 8 days of treatment of MOLM13 and MV4;11 cells with MI-3454, Gilt, or their combination. (D) Flow cytometric quantification of differentiation markers (CD11b+ and CD14+) in MV4;11 cells after single-agent or combinatorial treatment with MI-3454 and Gilt. (E) Gene expression studies in MV4;11 cells after 8 days of treatment with MI-3454, Gilt, or their combination. (A-E) Graphs are representative of 2 independent experiments performed in triplicate. (F-H) Comparison of differentially expressed (DE) genes (adjusted P < .05; fold change >|1.5|) from RNA sequencing (RNA-seq) studies in MOLM13 cells after 8 days of treatment with dimethyl sulfoxide (DMSO), MI-3454, Gilt, or their combination (n = 3 samples per treatment group). (F) Venn diagrams show the overlap of upregulated DE genes (right) and downregulated DE genes (left) relative to DMSO. (G) Heatmap of DE genes after k-means clustering of DE genes using a priori–determined 5 clusters. (H) Average z scores for all treatment groups calculated within each k-means cluster. (I) Summary of fast gene set enrichment analysis results for gene sets relating to targets of MYC, differentiation, or stemness from the RNA-seq studies in MOLM13. Each bubble represents a gene set. Size of bubbles on the plot indicates the level of significance, and y-axis indicates the normalized enrichment score (NES) for the gene sets. (J) Representative gene set enrichment plots for MYC targets for each treatment condition relative to DMSO for the Bild_Myc_Oncogenic_Signature gene set from MSigDB. The heatmaps show genes comprising the leading edge of the gene set enrichment plots. Red indicates high expression; blue indicates low expression; black arrows indicate MYC. *P < .05, **P < .01, ***P < .001, ****P < .0001 by 2- (A-B) or 1-way (C-E) analysis of variance with Tukey multiple comparison test. adj, adjusted; ES, enrichment score.

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