Fig. 4: CALR driver mutations sensitize MF HSPCs to BET inhibition.

A BET and HDAC inhibitor HSPC responses across the cohort split by driver mutation (MF CALR, n = 14 patients; MF JAK2, n = 26 patients). Responder = significant (p < 0.05) on-target response, non-responder = non-significant on-target, resistant = off-target response. B Signed ANOVA significance of BET and HDAC inhibitor HSPC drug responses to clinical parameters. C BET inhibitor drug responses of a co-cultured CALR CRISPRed cell line panel analyzed by pharmacoscopy. A representative experiment of two is shown, with two technical replicates across two conditions with 25 images per well. The y-axis depicts the change in relative fraction per cell line in the drug-treated condition compared to DMSO. p-Values indicate significance as determined by the Student’s t-test of CALR MUT depletion across the different replicates and concentrations compared to DMSO-treated cells. D Analysis of protein processes significantly up- or downregulated in BET (left) and HDAC inhibitor (right) responding patients. t-Tests were performed for each protein, comparing protein levels in HSPCs of responding MF patients compared to the non-responding and resistant patients. GSEA was performed on proteins ranked according to signed t-test significance. GSEA normalized enrichment scores (NES; x-axis) and enrichment significance (y-axis) are shown. E HSPC protein levels of selected Ras signaling pathway members. Patients are grouped according to HSPC response to BET and HDAC inhibitors (Responder, n = 28; resistant/non-responder, n = 22). Protein expression (y-axis) of proteins shown is significantly different for responders for at least 3 BET/HDAC inhibitors. p-Values indicate the Student’s t-test significance. Boxplots as in Fig. 1a. F Analysis of protein process–drug response associations of Bcl-2 inhibitors as in (D). 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. See also Supplementary Figs. 3 and 4.