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. Disclosures No relevant conflicts of interest to declare.