Models of LCH DC differentiation. (A) Previous studies support a model of LCH ontogeny where activating MAPK pathway gene mutation (bolt) in hematopoietic stem and precursor cells (gray) drive LCH lesion formation.^3,17,47  This study adds to previous reports by demonstrating HLA-DQB2 (purple surface icon) expression on blood CD1c⁺ mDCs with BRAFV600E⁺ in patients with high-risk LCH. Within LCH lesions, the presence of BRAFV600E and HLADQB2 in CD1c⁺ mDCs, CD1a⁺CD207⁻ cells, CD1a⁺CD207^low cells, and CD1a⁺CD207^high cells is consistent with differentiation of the CD1c⁺ mDC precursor from blood into lesion DCs. A logical pathway (solid black arrow) would lead to acquisition of CD1a, then CD207 expression; however, it is also possible that these populations may exist in equilibrium (dashed red arrow) at different stages of terminal differentiation based on environmental cues. Although data from this study support origin of LCH CD1a⁺CD207⁺ DCs from blood CD1c⁺ mDCs, it remains possible that some LCH DCs may arise from blood CD14⁺ monocytes, though lack of BRAFV600E⁺CD14⁺ cells in lesions would require these cells to rapidly differentiate (dashed black arrow) or represent a minor fraction of LCH lesion cells below the limits of detection. (B) This schema shows the Misguided Myeloid Differentiation Model for LCH ontogeny for different risk groups, augmented with data from this study.¹  According to this model, the stage of differentiation in which myeloid cell acquires BRAFV600E mutation (or alternative activating MAPK gene mutations) determines the extent of LCH (high- or low-risk LCH). High-risk multisystem LCH arises from activating the MAPK gene mutation of hematopoietic stem/progenitor cells from bone marrow (BM); the low-risk multisystem LCH arises from somatic mutation of committed DC precursor cells in blood; and low-risk single system LCH arises from somatic mutation of more differentiated DC precursors from blood. Although the stage of differentiation in which myeloid cells acquire mutation defines LCH clinical manifestation, data from this study are consistent with blood-derived CD1c⁺ mDCs migrating to lesion sites and differentiating into pathologic CD1a⁺CD207⁺ LCH cells. VAF, variant allele frequency.