Editors' ChoiceLeukemia

A Hair-Raising Finding in Leukemia

Science Translational Medicine  29 Jun 2011:
Vol. 3, Issue 89, pp. 89ec99
DOI: 10.1126/scitranslmed.3002799


Although hairy cell leukemia (HCL) has been recognized as a distinct disease for more than 50 years, the genetic alterations that underpin this disease are unknown. There are several hurdles to the molecular characterization of HCL, including the scarcity of tumor cells, their low proliferation rate, and the inability to grow them in animal models. In a recent report, Tiacci et al. now tackle this problem using whole-exome sequencing of HCL cells, and the molecular pathway they uncover reveals a new treatment option for this disease.

The researchers sequenced the exomes of leukemic cells and matched normal cells from an index patient with HCL. Their analysis led to the discovery of a heterozygous mutation in the BRAF gene that results in a kinase protein containing an amino acid switch at position 600 (V600E). The BRAF V600E mutation has so far only been identified in solid tumors such as melanoma and thyroid tumors. Using Sanger sequencing, the authors verified the presence of the V600E BRAF mutation in leukemic cells from 47 other patients with HCL. None of the 195 cell samples from patients with B-cell lymphoma or other types of leukemia carried this mutation. Western blotting and immunohistochemistry of HCL cells showed that two kinases (MEK and ERK) acting downstream of BRAF kinase are phosphorylated, suggesting constitutive activation of the RAF-MEK-ERK-MAPK growth signaling pathway. The investigators then treated leukemic cells from five HCL patients in vitro with the BRAF inhibitor PLX-4720, which has shown promise for treating metastatic melanoma. Treatment with this BRAF inhibitor led to a marked reduction in the phosphorylation of MEK and ERK, with a concomitant decrease in the activation of the RAF signaling pathway.

This study not only expands our knowledge of HCL pathogenesis, but also paves the way for using BRAF inhibitors to treat this disease. In addition, the unexpected finding of the V600E BRAF mutation in HCL suggests that this mutation should be sought in other cancers for which a disease-causing mutation has not yet been identified.

E. Tiacci et al., BRAF mutations in hairy-cell leukemia. N. Engl. J. Med. 364, 2305–2315 (2011). [Abstract]