BRAF inhibitors reverse the unique molecular signature and phenotype of hairy cell leukemia and exert potent antileukemic activity

airy cell leukemia (HCL) is a mature B-cell malignancy with unique clinicopathological, im munophenotypic, and gene expression features among other B-cell leukemias/lymphomas. 1-5 Patients with HCL typically present with pancytopenia, splenomegaly in the absence of signi fi cant lymphadenopathy, and in fi ltration of the bone marrow, spleen, and liver by leukemic cells with peculiar hairy projections emanating from their cell membrane. These leukemic hairy cells circulate usually in low numbers in the peripheral blood and are dif fi cult to aspirate from the bone marrow due to HCL-induced marrow fi brosis. 1,4 HCL responds well to chemotherapy with the purine analogs cladribine and pentostatin, but ; 40% of patients relapse and become progressively less responsive to these myelotoxic and immune-suppressive drugs. 6,7 Thus, new therapeutic approaches are needed. Recently, by whole-exome sequencing, we discovered the genetic lesion underlying HCL, that is, the V600E phosphomimetic substitution in the activation segment of the BRAF kinase domain. 8 The BRAF-V600E mutation de fi nes HCL among B-cell leukemias and lymphomas, as it is clonally present in almost 100% of HCL patients and in almost no patients with other B-cell malignancies. 8-