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

Abstract

Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD) are rare histiocytic disorders induced by somatic mutation of MAPK pathway genes. BRAF V600E 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, BRAF V600E allele-specific polymerase chain reaction was used to map the neoplastic clone in 20 adults with LCH, ECD, and HCL. BRAF V600E was tracked to classical monocytes, nonclassical monocytes, and CD1c 1 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 BRAF V600E 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 1 DCs acquired high langerin and CD1a with granulocyte-macrophage colony-stimulating factor and transforming growth factor b alone, whereas CD14 1 classical monocytes required additional notch ligation. Both classical and nonclassical monocytes, but not CD1c 1 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. (Blood. 2017;130(2):167-175)

Human dendritic cell subsets: an update

“…[176][177][178] Myeloid cDC2, however, rapidly up-regulate langerin to high levels and form Birbeck granules with GM-CSF or TSLP and TGF-b or BMP7. 133,134,179 In vivo evidence for these two pathways has recently been reported in the homeostasis of mucosal LC 164 but direct evidence is lacking in humans.…”

Langerhans cell histiocytosis in adults: Advances in pathophysiology and treatment

“…BRAF ‐V600E has been shown to be present in hematopoietic stem cells and myeloid progenitors in the bone marrow of high‐risk LCH patients. Additionally, CD1c+ dendritic cells have been shown to acquire high CD1a and CD207 expression with granulocyte‐macrophage colony‐stimulating factor and transforming growth factor‐beta alone in vitro . In contrast, classical CD14+ monocytes required additional notch ligation.…”

“…35 Berres et al 13 and transforming growth factor-beta alone in vitro. 36 In contrast, 37 Constitutive activation of the MAPK pathway due to BRAF mutation plays a critical role in LCH. A previous study identified BRAF-V600E in CD34+ cells in patients with hairy cell leukemia.…”

Erdheim-Chester disease associated with chronic myelomonocytic leukemia harboring the same clonal mutation

“…12 Additionally, two recent studies highlighted that the cell of origin of one third of patients with systemic histiocytosis resides in CD34 + hematopoietic progenitor cells prior to committed monocytes/macrophages. 13,14 Two main biologic mechanisms might explain the link between CMML and ECD. The first one would be a differentiation from a clonal CMML cell into foamy…”