Fig. 8: Homozygous CALR mutations lead to ER stress-associated vulnerabilities.
From: Proteogenetic drug response profiling elucidates targetable vulnerabilities of myelofibrosis

A Gene set enrichment analysis (GSEA) of ranked correlations between granulocyte protein levels and CALR/JAK2 granulocyte VAF. KEGG terms with an adjusted enrichment p < 0.0001 are shown. B Protein–protein interaction network of proteins significantly correlating to CALR VAF. Proteins with significant Pearson correlations are shown (p < 0.01). Edges: physical interaction STRING score > 0.7. Node color: Pearson correlations; Outer rings: selected protein pathway memberships. Blue shading indicates the interaction cluster of CALR and associated ER proteins. C Heatmap of ER stress cluster protein expression levels across MF patient granulocytes. Patient VAF and protein class are indicated. D Volcano plot of MF CALR homozygous versus all other MF CALR proteotypes. Proteins are colored green and annotated if significantly different and previously described to be upregulated in ER-stressed cell lines41. E Heatmap of ER stress cluster protein expression levels across cell types and cell lines. Protein levels normalized as log2FC as indicated in the legend. F Single-cell expression levels of CALRm correlated with HSPA5 across PBMCs of two MF CALR patients. Representative images (left panel) and quantification (right panel) of four replicate wells with 25 images per well are shown. Representative results of two independent repeats are shown. Pearson correlation and significance are reported. G Significance of depletion of CALR mutant expressing cells by ER stress inducers and UPR inhibitors across two MF CALR patient samples. The dashed line represents the diagonal. H Comparison of oncogenic drug responses between MF CALR homozygous and either MF CALR heterozygous (x-axis) or MF JAK2 (y-axis). Axes indicate an averaged difference in signed −log10 significances. Selected drugs are labeled and colored by drug class. I Oncogenic drug responses correspond to selected MF CALR homozygous-specific drug responses shown in (H). Boxplots indicate the range of drug responses across the MF cohort, dots represent individual patients. J Carfilzomib responses of FACS-isolated CD34+ MF patient HSPCs. Boxplots represent log2FC differences between DMSO- and drug-treated conditions. Asterisks indicate non-adjusted two-sided Student’s t-test significance: **** = p < 0.0001, ** = p < 0.01, * = p < 0.05; exact p-values are reported in Source Data. Boxplots as in Fig. 1A. See also Supplementary Fig. 7.