Potential precursor pathways in MS-LCH and ECD. Schema summarizing potential precursor pathways in MS-LCH and ECD based on the distribution of BRAF^V600E alleles in peripheral blood and the differentiation potentials of healthy control cells in vitro. A minority of cells (filled) in the BM and blood contain BRAF mutation. The principal observation is that <1% clonal hematopoiesis gives rise to <3% mutated blood precursors that appear to be strongly selected for in peripheral tissue environments, resulting in lesional histiocyte mutation levels of up to 100%. Lesions potentially consist of >1 precursor as indicated by blue for CD1c⁺ DCs, red for classical monocytes, and brown for nonclassical monocytes. The depiction of lesion composition is conjectural and not based on experimental observation. Furthermore, additional contributions from other, more primitive myeloid progenitors cannot be excluded at present.