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

Blood. 2017 Jul 13;130(2):176-180. doi: 10.1182/blood-2016-12-757377. Epub 2017 May 31.

Abstract

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 MAPK 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 MAPK 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.

MeSH terms

  • Adult
  • Alleles
  • Animals
  • Antigens, CD34 / genetics
  • Antigens, CD34 / immunology
  • Bone Marrow Cells / immunology
  • Bone Marrow Cells / pathology*
  • Bone Marrow Transplantation
  • Cell Differentiation
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / immunology
  • Dendritic Cells / immunology
  • Dendritic Cells / pathology
  • Dioxygenases
  • Erdheim-Chester Disease / genetics
  • Erdheim-Chester Disease / immunology
  • Erdheim-Chester Disease / pathology*
  • Gene Expression
  • Hematopoietic Stem Cells / immunology
  • Hematopoietic Stem Cells / pathology*
  • Histiocytosis, Langerhans-Cell / genetics
  • Histiocytosis, Langerhans-Cell / immunology
  • Histiocytosis, Langerhans-Cell / pathology*
  • Humans
  • Immunophenotyping
  • Macrophages / immunology
  • Macrophages / pathology
  • Mice
  • Monocytes / immunology
  • Monocytes / pathology
  • Mutation
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / immunology
  • Proto-Oncogene Proteins B-raf / genetics*
  • Proto-Oncogene Proteins B-raf / immunology
  • Transplantation, Heterologous

Substances

  • Antigens, CD34
  • DNA-Binding Proteins
  • Proto-Oncogene Proteins
  • Dioxygenases
  • TET2 protein, human
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf