Hematopoietic origin of Langerhans cell histiocytosis and Erdheim-Chester disease in adults

Blood. 2017 Jul 13;130(2):167-175. doi: 10.1182/blood-2016-12-757823. Epub 2017 May 16.

Abstract

Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD) are rare histiocytic disorders induced by somatic mutation of MAPK pathway genes. BRAFV600E mutation is the most common mutation in both conditions and also occurs in the hematopoietic neoplasm hairy cell leukemia (HCL). It is not known if adult LCH or ECD arises from hematopoietic stem cells (HSCs), nor which potential blood borne precursors lead to the formation of histiocytic lesions. In this study, BRAFV600E allele-specific polymerase chain reaction was used to map the neoplastic clone in 20 adults with LCH, ECD, and HCL. BRAFV600E was tracked to classical monocytes, nonclassical monocytes, and CD1c+ myeloid dendritic cells (DCs) in the blood, and mutations were observed in HSCs and myeloid progenitors in the bone marrow of 4 patients. The pattern of involvement of peripheral blood myeloid cells was indistinguishable between LCH and ECD, although the histiocytic disorders were distinct to HCL. As reported in children, detection of BRAFV600E in peripheral blood of adults was a marker of active multisystem LCH. The healthy counterparts of myeloid cells affected by BRAF mutation had a range of differentiation potentials depending on exogenous signals. CD1c+ DCs acquired high langerin and CD1a with granulocyte-macrophage colony-stimulating factor and transforming growth factor β alone, whereas CD14+ classical monocytes required additional notch ligation. Both classical and nonclassical monocytes, but not CD1c+ DCs, made foamy macrophages easily in vitro with macrophage colony-stimulating factor and human serum. These studies are consistent with a hematopoietic origin and >1 immediate cellular precursor in both LCH and ECD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Alleles
  • Antigens, CD / genetics
  • Antigens, CD / immunology
  • Antigens, CD1 / genetics
  • Antigens, CD1 / immunology
  • Bone Marrow Cells / immunology
  • Bone Marrow Cells / pathology*
  • Cell Differentiation
  • Dendritic Cells / immunology
  • Dendritic Cells / pathology
  • Diagnosis, Differential
  • Erdheim-Chester Disease / diagnosis*
  • Erdheim-Chester Disease / genetics
  • Erdheim-Chester Disease / immunology
  • Erdheim-Chester Disease / pathology
  • Female
  • Foam Cells / immunology
  • Foam Cells / pathology
  • Gene Expression
  • Glycoproteins / genetics
  • Glycoproteins / immunology
  • Granulocyte-Macrophage Colony-Stimulating Factor / genetics
  • Granulocyte-Macrophage Colony-Stimulating Factor / immunology
  • Hematopoietic Stem Cells / immunology
  • Hematopoietic Stem Cells / pathology*
  • Histiocytosis, Langerhans-Cell / diagnosis*
  • Histiocytosis, Langerhans-Cell / genetics
  • Histiocytosis, Langerhans-Cell / immunology
  • Histiocytosis, Langerhans-Cell / pathology
  • Humans
  • Immunophenotyping
  • Lectins, C-Type / genetics
  • Lectins, C-Type / immunology
  • Lipopolysaccharide Receptors / genetics
  • Lipopolysaccharide Receptors / immunology
  • Male
  • Mannose-Binding Lectins / genetics
  • Mannose-Binding Lectins / immunology
  • Monocytes / immunology
  • Monocytes / pathology
  • Mutation
  • Proto-Oncogene Proteins B-raf / genetics*
  • Proto-Oncogene Proteins B-raf / immunology
  • Receptors, Notch / genetics
  • Receptors, Notch / immunology
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / immunology

Substances

  • Antigens, CD
  • Antigens, CD1
  • CD1C protein, human
  • CD1a antigen
  • CD207 protein, human
  • Glycoproteins
  • Lectins, C-Type
  • Lipopolysaccharide Receptors
  • Mannose-Binding Lectins
  • Receptors, Notch
  • Transforming Growth Factor beta
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf