Vemurafenib silences the transcriptional output of the BRAF-MEK-ERK pathway in HCL and the whole expression signature distinguishing HCL from normal B cells and other B-cell neoplasms. (A) The overall expression of the 48 genes induced by the BRAF-MEK-ERK pathway in melanoma and colorectal carcinoma²⁰  is considerably depleted in the profiles of HCL cells treated for 48 and/or 72 hours with vemurafenib (13 samples from 6 patients) vs drug vehicle (11 samples from the same 6 patients), according to GSEA. (B) Color-coded heat map showing, in the individual HCL samples, the expression (red = high; blue = low) of these 48 genes, ranked by their signal-to-noise ratio (the default GSEA metric) in vemurafenib-treated vs vehicle-treated samples. (C) Color-coded expression heat map of genes significantly modulated (twofold change, corrected P < .05) in HCL cells from 6 patients (A-F) treated with vemurafenib 1 µM vs DMSO for 48 and/or 72 hours. (D) The overall expression of the HCL-specific signature (distinguishing HCL from normal B cells and other B-cell neoplasms³ ) is considerably depleted in the profiles of HCL cells (from 6 patients) treated with vemurafenib vs drug vehicle (DMSO) for 48 and/or 72 hours, according to GSEA.¹⁹  NES, normalized enrichment score.