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

Marie Luise Berres, Karen Phaik Har Lim, Tricia Peters, Jeremy Price, Hitoshi Takizawa, Hélène Salmon, Juliana Idoyaga, Albert Ruzo, Philip J. Lupo, M. John Hicks, Albert Shih, Stephen J. Simko, Harshal Abhyankar, Rikhia Chakraborty, Marylene Leboeuf, Monique Beltrão, Sérgio A. Lira, Kenneth M. Heym, Venetia Bigley, Matthew CollinMarkus G. Manz, Kenneth McClain, Miriam Merad, Carl E. Allen

Research output: Contribution to journalArticlepeer-review

290 Scopus citations

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 BRAFV600E 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.

Original languageEnglish
Pages (from-to)669-683
Number of pages15
JournalJournal of Experimental Medicine
Volume211
Issue number4
DOIs
StatePublished - Apr 2014

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