Functional evidence for derivation of systemic histiocytic neoplasms from hematopoietic stem/progenitor cells

Benjamin H. Durham, Damien Roos-Weil, Claude Baillou, Fleur Cohen-Aubart, Akihide Yoshimi, Makoto Miyara, Matthias Papo, Zofia Hélias-Rodzewicz, Nathalie Terrones, Neval Ozkaya, Ahmet Dogan, Raajit Rampal, Fanny Urbain, Lucie Le Fèvre, Eli L. Diamond, Christopher Y. Park, Thomas Papo, Frédéric Charlotte, Guy Gorochov, Valérie Taly, Olivier A. Bernard, Zahir Amoura, Omar Abdel-Wahab, François M. Lemoine, Julien Haroche and Jean-Francois Emile

Key points

  • BRAFV600E mutations are detectable in hematopoietic stem and progenitors in adults with histiocytosis.

  • Transplantation of CD34+ cells from histiocytosis patients can give rise to genetically and phenotypically accurate xenografts.


Langerhans Cell Histiocytosis (LCH) and the non-LCH neoplasm Erdheim-Chester Disease (ECD) are heterogeneous neoplastic disorders marked by infiltration of pathologic macrophage-, dendritic cell-, or monocyte-derived cells in tissues driven by recurrent mutations activating MAP kinase signaling. Although recent data indicate that at least a proportion of LCH and ECD patients have detectable activating kinase mutations in circulating hematopoietic cells and bone marrow-based hematopoietic progenitors, functional evidence of the cell-of-origin of histiocytosis from actual patient materials has long been elusive. Here we provide evidence for mutations in MAP kinase signaling intermediates in CD34+ cells from patients with ECD and LCH/ECD, including detection of shared origin of LCH and acute myelomonocytic leukemia driven by TET2-mutant CD34+ cell progenitors in one patient. We also demonstrate functional self-renewal capacity for CD34+ cells to drive the development of histiocytosis in xenotransplantation assays in vivo. These data indicate that the cell-of-origin of at least a proportion of patients with systemic histiocytoses resides in hematopoietic progenitor cells prior to committed monocyte/macrophage or dendritic cell differentiation and provide the first example of a patient-derived xenotransplantation model for a human histiocytic neoplasm.

  • Submitted December 16, 2016.
  • Accepted May 16, 2017.