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

  • Berres, Marie-Luise Department of Oncological Sciences, Tisch Cancer Institute, and Immunology Institute, Mount Sinai School of Medicine, New York, NY 10029
  • Lim, Karen Phaik Har Texas Children’s Cancer Center, Texas Children’s Hospital, Houston, TX 77030
  • Peters, Tricia Department of Pathology and Immunology; and Division of Pediatric Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030
  • Price, Jeremy Department of Oncological Sciences, Tisch Cancer Institute, and Immunology Institute, Mount Sinai School of Medicine, New York, NY 10029
  • Takizawa, Hitoshi Division of Hematology, University Hospital Zurich, 8091 Zurich, Switzerland
  • Salmon, Hélène Department of Oncological Sciences, Tisch Cancer Institute, and Immunology Institute, Mount Sinai School of Medicine, New York, NY 10029
  • Idoyaga, Juliana Laboratory of Stem Cell Biology and Molecular Embryology, Laboratory of Cellular Physiology and Immunology, and Chris Browne Center for Immunology and Immune Diseases, The Rockefeller University, New York, NY 10065
  • Ruzo, Albert Laboratory of Stem Cell Biology and Molecular Embryology, Laboratory of Cellular Physiology and Immunology, and Chris Browne Center for Immunology and Immune Diseases, The Rockefeller University, New York, NY 10065
  • Lupo, Philip J. Department of Pathology and Immunology; and Division of Pediatric Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030
  • Hicks, M. John Department of Pathology and Immunology; and Division of Pediatric Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030
  • Shih, Albert Texas Children’s Cancer Center, Texas Children’s Hospital, Houston, TX 77030
  • Simko, Stephen J. Department of Pathology and Immunology; and Division of Pediatric Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030
  • Abhyankar, Harshal Department of Pathology and Immunology; and Division of Pediatric Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030
  • Chakraborty, Rikhia Department of Pathology and Immunology; and Division of Pediatric Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030
  • Leboeuf, Marylene Department of Oncological Sciences, Tisch Cancer Institute, and Immunology Institute, Mount Sinai School of Medicine, New York, NY 10029
  • Beltrão, Monique Department of Oncological Sciences, Tisch Cancer Institute, and Immunology Institute, Mount Sinai School of Medicine, New York, NY 10029
  • Lira, Sérgio A. Department of Oncological Sciences, Tisch Cancer Institute, and Immunology Institute, Mount Sinai School of Medicine, New York, NY 10029
  • Heym, Kenneth M. Cook Children’s Medical Center, Fort Worth, TX 76104
  • Clausen, Björn E. Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany
  • Bigley, Venetia Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, England, UK
  • Collin, Matthew Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, England, UK
  • Manz, Markus G. Division of Hematology, University Hospital Zurich, 8091 Zurich, Switzerland
  • McClain, Kenneth Department of Pathology and Immunology; and Division of Pediatric Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030
  • Merad, Miriam Department of Oncological Sciences, Tisch Cancer Institute, and Immunology Institute, Mount Sinai School of Medicine, New York, NY 10029
  • Allen, Carl E. Department of Pathology and Immunology; and Division of Pediatric Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030
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  • 2014-3-17
Published in:
  • Journal of Experimental Medicine. - Rockefeller University Press. - 2014, vol. 211, no. 4, p. 669-683
Immunology
Immunology and Allergy
English 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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  • English
Open access status
hybrid
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https://sonar.ch/global/documents/235708
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