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

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          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.

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          Author and article information

          Journal
          J Exp Med
          J. Exp. Med
          jem
          jem
          The Journal of Experimental Medicine
          The Rockefeller University Press
          0022-1007
          1540-9538
          7 April 2014
          : 211
          : 4
          : 669-683
          Affiliations
          [1 ]Department of Oncological Sciences , [2 ]Tisch Cancer Institute , and [3 ]Immunology Institute, Mount Sinai School of Medicine, New York, NY 10029
          [4 ]Texas Children’s Cancer Center, Texas Children’s Hospital, Houston, TX 77030
          [5 ]Department of Pathology and Immunology ; and [6 ]Division of Pediatric Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030
          [7 ]Division of Hematology, University Hospital Zurich, 8091 Zurich, Switzerland
          [8 ]Laboratory of Stem Cell Biology and Molecular Embryology , [9 ]Laboratory of Cellular Physiology and Immunology , and [10 ]Chris Browne Center for Immunology and Immune Diseases, The Rockefeller University, New York, NY 10065
          [11 ]Cook Children’s Medical Center, Fort Worth, TX 76104
          [12 ]Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, England, UK
          Author notes
          CORRESPONDENCE Carl Allen: ceallen@ 123456txch.org OR Miriam Merad: miriam.merad@ 123456mssm.edu

          M.-L. Berres, K.P.H. Lim, and T. Peters contributed equally to this paper.

          Article
          20130977
          10.1084/jem.20130977
          3978272
          24638167
          © 2014 Berres et al.

          This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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