Cell of origin of hairy cell leukemia

Hairy cell leukemia (HCL) is a B cell malignancy in which leukemic cells express mature B cell surface markers and have clonal rearrangements of immunoglobulin genes. Although a somatic BRAF^V600E alteration occurs in nearly all cases of HCL, the cell of origin of this type of leukemia has not been definitively identified. Now, Omar Abdel-Wahab, Christopher Park and colleagues identify hematopoietic stem cells (HSCs) as the preleukemic cell of origin for HCL (Sci. Transl. Med. 6, 238ra71, 2014). They used flow sorting of 14 HCL clinical samples and 3 age-matched controls to isolate cell populations along the hematopoietic hierarchy and assayed for the BRAF^V600E alteration in each sorted fraction, identifying BRAF^V600E in the HSC, pro-B cell and HCL cell populations from HCL samples. The presence of the alteration in phenotypically normal HSCs suggests that these cells are a preleukemic ancestral cell type. They also found that these BRAF^V600E-bearing HSCs did not carry additional mutations present in leukemic cells. The authors then used mouse models to show that expression of BRAF^V600E in HSCs caused a lethal hematopoietic disorder similar to HCL, whereas targeting its expression to the B cell lineage caused no hematopoietic abnormalities.