Sezary syndrome originates from heavily mutated hematopoietic progenitors

The pathogenesis of cutaneous T-cell lymphoma (CTCL) remains unclear. Using single-cell RNA or T-cell receptor (TCR) sequencing of 32 619 CD3+CD4+ and CD26+/CD7+ and 29 932 CD3+CD4+ and CD26-/CD7- lymphocytes from the peripheral blood of 7 patients with CTCL, coupled to single-cell ATAC-sequencing of 26,411 CD3+CD4+ and CD26+/CD7+ and 33 841 CD3+CD4+ and CD26-/CD7- lymphocytes, we show that tumor cells in S e ' zary syndrome and mycosis fungoides (MF) exhibit different phenotypes and trajectories of differentiation. When compared to MF, Se ' zary cells exhibit narrower repertoires of TCRs and exhibit clonal enrichment. Surprisingly, we identified >= 200 mutations in hematopoietic stem cells from multiple patients with S e ' zary syndrome. Mutations in key oncogenes were also present in peripheral S e ' zary cells, which also showed the hallmarks of recent thymic egression. Together our data suggest that CTCL arises from mutated lymphocyte progenitors that acquire TCRs in the thymus, which complete their malignant transformation in the periphery.

Automated summary

This study reveals the pathogenesis of cutaneous T-cell lymphoma (CTCL) using single-cell sequencing techniques. The findings show that tumor cells in Se'zary syndrome and mycosis fungoides (MF) exhibit different phenotypes and differentiation trajectories. Additionally, it is discovered that Se'zary cells have narrower T-cell receptor repertoires and clonal enrichment compared to MF. Furthermore, mutations in key oncogenes are present in peripheral Se'zary cells, indicating recent thymic egression. The data suggest that CTCL originates from mutated lymphocyte progenitors and completes malignant transformation in the peripheral blood.