Proposed model of the evolution of MF. Skin lesions of MF are formed by seeding with the circulating malignant T-cell clones, which undergo further mutational evolution. (A) It is likely malignant clones originate from an immature T cell transformed before TCRB rearrangement and therefore show clonotypic heterogeneity (highlighted by different colors of the cytoplasm). (B) These circulating neoplastic T cells undergo expansion and accumulate mutations, leading to emergence of genetically different malignant subclones (different colors of the nucleus). Some of the circulating malignant cells seed into the skin (stippled gray arrows) (C), where they proliferate, accumulate additional mutations, and develop additional subclones as the disease progresses (D). (E) Some subclones may reenter the circulation and seed other skin lesions (red stippled arrow), further increasing the heterogeneity of the lesions and causing disease progression. Solid lines symbolize the phylogenetic relationship between generations of malignant cells that follow the pattern of divergent, neutral evolution. Data from this study and our previous work.^7,29,50,51