• 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 Collin, Markus G Manz, Kenneth McClain, Miriam Merad, and Carl E Allen.
• Department of Oncological Sciences, 2 Tisch Cancer Institute, and 3 Immunology Institute, Mount Sinai School of Medicine, New York, NY 10029.
• J. Exp. Med. 2014 Apr 7; 211 (4): 669-83.

AbstractLangerhans 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.

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