BRAF-V600E expression in precursor versus differentiated dendritic cells defines clinically distinct LCH risk groups

Abstract

BRAF-V600E expression is identified in hematopoietic progenitor and precursor myeloid dendritic cells in patients with high-risk LCH, and enforced expression of BRAF-V600E in CD11c ⁺ cells recapitulates a high-risk LCH-like phenotype in mice.

Abstract

Langerhans cell histiocytosis (LCH) is a clonal disorder with elusive etiology, characterized by the accumulation of CD207 ⁺ dendritic cells (DCs) in inflammatory lesions. Recurrent BRAF-V600E mutations have been reported in LCH. In this study, lesions from 100 patients were genotyped, and 64% carried the BRAF-V600E mutation within infiltrating CD207 ⁺ DCs. BRAF-V600E expression in tissue DCs did not define specific clinical risk groups but was associated with increased risk of recurrence. Strikingly, we found that patients with active, high-risk LCH also carried BRAF-V600E in circulating CD11c ⁺ and CD14 ⁺ fractions and in bone marrow (BM) CD34 ⁺ hematopoietic cell progenitors, whereas the mutation was restricted to lesional CD207 ⁺ DC in low-risk LCH patients. Importantly, BRAF-V600E expression in DCs was sufficient to drive LCH-like disease in mice. Consistent with our findings in humans, expression of BRAF-V600E in BM DC progenitors recapitulated many features of the human high-risk LCH, whereas BRAF-V600E expression in differentiated DCs more closely resembled low-risk LCH. We therefore propose classification of LCH as a myeloid neoplasia and hypothesize that high-risk LCH arises from somatic mutation of a hematopoietic progenitor, whereas low-risk disease arises from somatic mutation of tissue-restricted precursor DCs.