Hairy cell leukemia (HCL) shows unique clinicopathological and biological 
features. HCL responds well to purine analogs but relapses are frequent and 
novel therapies are required. BRAF-V600E is the key driver mutation in HCL and 
distinguishes it from other B-cell lymphomas, including HCL-like 
leukemias/lymphomas (HCL-variant and splenic marginal zone lymphoma). The 
kinase-activating BRAF-V600E mutation also represents an ideal therapeutic 
target in HCL. Here, we investigated the biological and therapeutic importance 
of the activated BRAF-mitogen-activated protein kinase kinase 
(MEK)-extracellular signal-regulated kinase (ERK) pathway in HCL by exposing in 
vitro primary leukemic cells purified from 26 patients to clinically available 
BRAF (vemurafenib; dabrafenib) or MEK (trametinib) inhibitors. Results were 
validated in vivo in samples from vemurafenib-treated HCL patients within a 
phase 2 clinical trial. BRAF and MEK inhibitors caused, specifically in HCL (but 
not HCL-like) cells, marked MEK/ERK dephosphorylation, silencing of the 
BRAF-MEK-ERK pathway transcriptional output, loss of the HCL-specific gene 
expression signature, downregulation of the HCL markers CD25, tartrate-resistant 
acid phosphatase, and cyclin D1, smoothening of leukemic cells' hairy surface, 
and, eventually, apoptosis. Apoptosis was partially blunted by coculture with 
bone marrow stromal cells antagonizing MEK-ERK dephosphorylation. This 
protective effect could be counteracted by combined BRAF and MEK inhibition. Our 
results strongly support and inform the clinical use of BRAF and MEK inhibitors 
in HCL.