Transcriptional Profiles, Lineage Tracing with BRAF-V600E and HLA-DQB2 Expression Support a Model of Blood CD1c+ Cells As Precursors to LCH Lesion CD207+ Cells

Purpose: Langerhans Cell Histiocytosis (LCH) is characterized by granulomatous lesions that include pathologic CD1a⁺/CD207⁺dendritic cells (DC). Activating somatic MAPK pathway gene mutations have been identified in hematopoietic stem cells and lesion DCs in patients with high-risk LCH, though the differentiation pathway remains uncertain. The purpose of this study was to define the origin of LCH lesion CD1a⁺/CD207⁺ cells.

Methods: We compared transcriptomes of LCH lesion CD1a⁺/CD207⁺ cells to established gene signatures from human peripheral blood and tissue myeloid populations including CD14⁺ monocytes, CD16⁺ monocytes, CD14⁺ DCs, macrophages, epidermal Langerhans cells, CD1c⁺ myeloid dendritic cells (mDCs) and CD141⁺mDCs. Additionally, quantitative PCR of BRAF-V600E and HLA-DQB2, and HLA-DQB2 surface expression were used to identify clonal lesion and peripheral blood monocyte and dendritic cell populations.

Results: When comparing lesion CD1a⁺/CD207⁺ cells to blood and tissue DC/monocyte populations, the CD1c⁺ mDC gene signature was most similar to gene expression profile of lesion CD1a⁺/CD207⁺ cells. In order to further test the hypothesis that LCH CD1a⁺/CD207⁺ cells arise from CD1c⁺mDCs, we investigated subpopulations within the LCH lesions for the BRAF-V600E allele and found that, in addition to LCH CD1a⁺ and CD1a⁺/CD207⁺ DCs, BRAF-V600E was also identified in LCH lesional CD1c⁺ mDCs. Furthermore, HLA-DQB2, highly expressed in LCH CD1a⁺/CD207⁺ cells, was also expressed in LCH lesion CD1c⁺ cells, but not in any other lesion myeloid subpopulations. Furthermore, HLA-DQB2 was expressed only in peripheral blood of patients with active high-risk LCH, and HLA-DQB2⁺ CD1c⁺ blood cells were highly enriched for the BRAF-V600E allele.

Conclusion: These data support a model where blood CD1c⁺ mDCs with hyperactive ERK migrate to lesion sites and differentiate into LCH CD1a⁺/CD207⁺ cells. If differentiation from CD1c⁺ DCs to CD1a⁺/CD207⁺ cells is critical to LCH pathogenesis, blocking this process may represent a novel therapeutic opportunity.