Finding: BRAF V600E is the disease-defining genetic event in hairy-cell leukemia.
Approach: Massively parallel, whole-exome sequencing is used to characterize hairy-cell leukemia cells.
Impact: BRAF V600E identification will lead to more accurate diagnosis and additional therapeutic options.
Hairy-cell leukemia (HCL) is a hematologic malignancy characterized by bone marrow infiltration of abnormal B cells that possess hair-like cytoplasmic projections. The disease course tends to be indolent and the majority of patients achieve remission after monotherapy with a purine nucleoside analog, but the underlying genetic defect remains unknown. To investigate the genetic basis of HCL, Tiacci and colleagues performed genome-wide parallel DNA sequencing on tumor cells and normal cells collected from the same HCL patient. The most significant finding was a mutation in the BRAF gene that encodes the oncogenic BRAF V600E protein, commonly associated with melanoma and papillary thyroid cancers. Importantly, an additional 47 HCL patients were then screened and 100% were found to express V600E, whereas 195 patients with other peripheral B-cell lymphomas or leukemias did not carry the mutation. BRAF V600E is known to be a constitutively active variant of the BRAF protein kinase, part of the RAS/RAF/MAPK signaling pathway. MEK and ERK, 2 downstream targets of BRAF, were phosphorylated in the HCL cells, and the phosphorylation was decreased in the presence of a BRAF inhibitor. Taken together, the results of this study identify the BRAF V600E mutation as the disease-defining genetic event in HCL, a novel discovery that can be used both as a diagnostic tool to distinguish HCL from other B-cell malignancies as well as the basis for additional therapeutic targets, including BRAF inhibition.
Tiacci E, Trifonov V, Schiavoni G, Holmes A, Kern W, Martelli MP, et al. BRAF mutations in hairy-cell leukemia. N Engl J Med 2011;364:2305–15.
Note: Research Watch is written by Cancer Discovery Editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.