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

Paul Milne, Venetia Bigley, Chris M. Bacon, Antoine Néel, Naomi McGovern, Simon Bomken, Muzlifah Haniffa, Eli L. Diamond, Benjamin H. Durham, Johannes Visser, David Hunt, Harsha Gunawardena, Mac Macheta, Kenneth L. McClain, Carl Allen, Omar Abdel-Wahab and Matthew Collin

Key points

  • Bone marrow progenitors, monocytes and myeloid dendritic cells contain BRAFV600E alleles in adults with LCH and ECD

  • Mutant allele distribution is not disease-specific but precursors have distinct LCH-like and macrophage differentiation capacities


Langerhans cell histiocytosis (LCH) and Erdheim Chester Disease (ECD) are rare histiocytic disorders induced by somatic mutation of MAP kinase 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 arise from hematopoietic stem cells (HSC) nor which potential blood borne precursors lead to the formation of histiocytic lesions. In this study, BRAF V600E allele-specific PCR was used to map the neoplastic clone in 20 adults with LCH ECD and HCL. BRAFV600E was tracked to classical monocytes, non-classical monocytes and CD1c+ myeloid 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 multi-system LCH (MS-LCH). The healthy counterparts of myeloid cells affected by BRAF mutation had a range of differentiation potentials depending upon exogenous signals. CD1c+ DCs acquired high langerin and CD1a with GM-CSF and TGFβ alone while CD14+ classical monocytes required additional notch ligation. Both classical and non-classical monocytes, but not CD1c+ DCs made foamy macrophages easily in vitro with M-CSF and human serum (HS). These studies are consistent with a hematopoietic origin and more than one immediate cellular precursor, in both LCH and ECD.

  • Submitted December 16, 2016.
  • Accepted April 24, 2017.