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

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 -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.

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

“…Progenitor cells from this patient were demonstrated to engraft in immunodeficient mice, in the accompanying paper. 27 These results suggest that LCH and ECD arise in the HSCs and are transmitted to peripheral tissues by blood-borne myeloid cells. However, there was no obvious disease-specific bias in the distribution of mutant alleles among myeloid cells that might correlate phenotypic differences between LCH and ECD.…”

Langerhans cell histiocytosis in adults: Advances in pathophysiology and treatment

“…In contrast, classical CD14+ monocytes required additional notch ligation. A recent study revealed the self‐renewing capacity of CD34+ cells, which drives the development of histiocytosis in xenograft transplantation assays in vivo . Constitutive activation of the MAPK pathway due to BRAF mutation plays a critical role in LCH.…”

“…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.…”

Concomitant Erdheim‐Chester disease and chronic myelomonocytic leukaemia: genomic insights into a common clonal origin

“…However, both the bone marrow and skin tissue had several unique mutations. Additionally, in a recent report of a patient with concomitant mixed ECD/LCH and acute myelomonocytic leukaemia, the investigators found similar BRAF, TET2 and SRSF2 mutations in both the LCH tissue as well as the CD34+ progenitor cells in the bone marrow (Durham et al , ). Our data add to these findings and support the contention for a common clonal origin in the instances of co‐occurrence of these histiocytic and monocytic neoplasms.…”