Sézary syndrome originates from heavily mutated hematopoietic progenitors

• Published in: Blood advances Vol. 7; no. 18; pp. 5586 - 5602
• Main Authors: Harro, Carly M., Sprenger, Kimberly B., Chaurio, Ricardo A., Powers, John J., Innamarato, Patrick, Anadon, Carmen M., Zhang, Yumeng, Biswas, Subir, Mandal, Gunjan, Mine, Jessica A., Cortina, Carla, Nagy, Mate Z., Martin, Alexandra L., Handley, Katelyn F., Borjas, Gustavo J., Chen, Pei-Ling, Pinilla-Ibarz, Javier, Sokol, Lubomir, Yu, Xiaoqing, Conejo-Garcia, Jose R.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 26.09.2023; The American Society of Hematology
• Subjects: Dipeptidyl Peptidase 4; Humans; Lymphoid Neoplasia; Lymphoma, T-Cell, Cutaneous - genetics; Mycosis Fungoides - genetics; Mycosis Fungoides - pathology; Receptors, Antigen, T-Cell; Sezary Syndrome - genetics; Sezary Syndrome - pathology; Skin Neoplasms - genetics; Skin Neoplasms - pathology
• ISSN: 2473-9529; 2473-9537; 2473-9537
• DOI: 10.1182/bloodadvances.2022008562

•CTCL cells arise from mutated hematopoietic stem cells after thymic egression.•Clonally enriched CTCL cells carry these progenitor mutations. [Display omitted] 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 Sézary syndrome and mycosis fungoides (MF) exhibit different phenotypes and trajectories of differentiation. When compared to MF, Sézary cells exhibit narrower repertoires of TCRs and exhibit clonal enrichment. Surprisingly, we identified ≥200 mutations in hematopoietic stem cells from multiple patients with Sézary syndrome. Mutations in key oncogenes were also present in peripheral Sézary 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.