Fig. 7: Proliferative MCM-high MF responds to the targeting of survival signaling and DNA replication.

A Correlation of MCM4 and MCM7 protein levels across the granulocyte cohort. Levels normalized by subtracting the median HD expression. B ANOVA significance of averaged MCM4 and MCM7 protein level associations with clinical parameters across the MF cohort. The red color indicates a positive association with continuous parameters (PB blasts and age) or to the first term of discrete factors (mutation, sex, and treatment). C Z-score normalized MCM4 and MCM7 protein levels across MF patients stratified by PB blast counts (<1%, n = 64; 1–5%, n = 39; >5%, n = 6). p-Values indicate the Student’s t-test significance. D Protein–protein interaction network of the top-50 proteins correlating to MCM4 and MCM7 protein levels across T-cell, HSPC, and granulocyte proteotypes. Edges: STRING score > 0.7. Proteins colored by average Pearson correlation. E Pathway enrichment analysis results of the 50-protein signature. Significant positive KEGG term enrichments (p < 0.05) are shown. F Ranking of averaged MCM4 and MCM7 protein levels per cell type and MF patient for the 20 MF patients present in both the granulocyte and MF PBMC cohorts. G Quantification of the percentage of MCM7, Ki-67, and yH2Ax positive PBMCs. Dots summarize the staining quantification of 2–4 patients (brackets) per MCM group averaged across three replicate wells and 25 images per well. Bars indicate the average per group. H Representative images of in vitro HSPC DNA replication fork fibers (left panel) and corresponding quantification (right panel). Dots summarize average fiber lengths of HSPCs isolated from 1 to 6 patient samples (brackets) per MCM group with 93–370 fibers per sample. Bars indicate the average per group. I On-target HSPC drug responses correlated to the average expression of the 50-protein replicative signature. x-axis, Pearson correlations; y-axis, corresponding significance. J Scatterplots of the three highest correlating drug responses of (I). Linear fit (blue line) and 95% confidence intervals (gray area) are shown. Pearson correlation and significance are indicated. K Vosaroxin responses of FACS-isolated CD34 + MF patient HSPCs from three vosaroxin-sensitive patients. Asterisks indicate non-adjusted two-sided significance: **** = p < 0.0001, *** = p < 0.001, ** = p < 0.01, * = p < 0.05; exact p-values are reported in Source Data. Boxplots as in Fig. 1A. See also Supplementary Fig. 6.