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. 2024 Apr 29;12:RP90683. doi: 10.7554/eLife.90683

Figure 5. Identification of agents that synergize with WIN site inhibitors (WINi) in MLLr cells.

(A) Peak synergy (>0) and antagonism (<0) zero interaction potency (ZIP) delta (δ) scores from synergy assays in which MV4;11 cells were treated for 3 d with 49 unique dose combinations of C16 and the indicated compound of interest (n = 4). See Figure 5—source data 1 for numerical ZIP delta analysis output. (B) Heatmaps of MV4;11 cell growth inhibition at each dose of C16 and the indicated six compounds. The remaining five combinations tested are shown in Figure 5—figure supplement 1. (C) As in (A) but for MOLM13 cells. See Figure 5—source data 1 for numerical ZIP delta analysis output. (D) As in (B) but for MOLM13 cells. The remaining five combinations tested are shown in Figure 5—figure supplement 2. (E) Number of genes with significantly (false discovery rate [FDR] < 0.05) altered transcript levels following treatment of MV4;11 cells with C16 (100 nM), mivebresib (Mibv; 2.5 nM), or the combination for 48 hr, as determined by RNA-seq (n = 3). See Figure 5—source data 2 for complete output of RNA-seq analysis. (F) UpSet plot, showing the overlap of genes suppressed (left) or induced (right) in response to C16, mivebresib, or the combination. (G) UpSet plot, showing the breakdown of Reactome ‘Translation’ pathway genes suppressed in response to C16, mivebresib, or the combination. (H) Enrichment of Reactome Pathways in genes with increased transcripts following treatment of MV4;11 cells with C16, mivebresib, or the combination. See Figure 5—source data 3 for complete output of enrichment analyses.

Figure 5—source data 1. Peak synergy and antagonism scores for MV4:11 and MOLM13 cells treated with C16 in combination with 11 agents.
Figure 5—source data 2. Output of RNA-seq analysis of MV4;11 cells treated with C16, mivebresib, or both.
Figure 5—source data 3. Enrichment analysis of differentially expressed genes in RNA-seq of MV4;11 cells treated with C16, mivebresib, or both.

Figure 5.

Figure 5—figure supplement 1. C16 is synergistic with multiple agents in MV4;11 cells.

Figure 5—figure supplement 1.

(A) Heatmaps of MV4;11 cell growth inhibition at each dose of C16 and the indicated five compounds. (B) Heatmaps of δ scores from MV4;11 cells at each dose combination of C16 and the indicated agents.
Figure 5—figure supplement 2. C16 is synergistic with multiple agents in MOLM13 cells.

Figure 5—figure supplement 2.

(A) Heatmaps of MOLM13 cell growth inhibition at each dose of C16 and the indicated five compounds. (B) Heatmaps of δ scores from MOLM13 cells at each dose combination of C16 and the indicated agents.
Figure 5—figure supplement 3. Impact of C16 and mivebresib on RPG and p53 target gene expression.

Figure 5—figure supplement 3.

(A) Transcript level changes in WDR5-bound (left) and non-bound (right) RPGs elicited by C16 (top), mivebresib (Mivb; middle), or the combination (bottom). (B) Heatmap, showing significant changes in the expression of consensus p53 target genes (Fischer, 2017) induced by C16, mivebresib (Mivb; middle) or the combination (bottom) in MV4;11 cells.