Marie-Luise Berres 1 , 2 , 3 , Karen Phaik Har Lim 4 , Tricia Peters 5 , Jeremy Price 1 , 2 , 3 , Hitoshi Takizawa 7 , Hélène Salmon 1 , 2 , 3 , Juliana Idoyaga 8 , 9 , 10 , Albert Ruzo 8 , Philip J. Lupo 4 , 6 , M. John Hicks 5 , Albert Shih 4 , Stephen J. Simko 4 , 6 , Harshal Abhyankar 4 , 6 , Rikhia Chakraborty 4 , 6 , Marylene Leboeuf 1 , 2 , 3 , Monique Beltrão 3 , Sérgio A. Lira 3 , Kenneth M. Heym 11 , Venetia Bigley 12 , Matthew Collin 12 , Markus G. Manz 7 , Kenneth McClain 4 , 6 , Miriam Merad , 1 , 2 , 3 , Carl E. Allen , 4 , 6
7 April 2014
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.
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.