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The Capital Region of Denmark - a part of Copenhagen University Hospital
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Skin colonization by circulating neoplastic clones in cutaneous T-cell lymphoma

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  • Aishwarya Iyer
  • Dylan Hennessey
  • Sandra O'Keefe
  • Jordan Patterson
  • Weiwei Wang
  • Gane Ka-Shu Wong
  • Robert Gniadecki
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Mycosis fungoides (MF) is a mature T-cell lymphoma currently thought to develop primarily in the skin by a clonal expansion of a transformed, resident memory T cell. However, this concept does not explain the key characteristics of MF, such as the debut with multiple, widespread skin lesions or inability of skin-directed therapies to provide cure. The testable inference of the mature T-cell theory is the clonality of MF with respect to all rearranged T-cell receptor (TCR) genes. Here, we used a whole-exome sequencing approach to detect and quantify TCR-α, β, and γ clonotypes in tumor cell clusters microdissected from MF lesions. This method allowed us to calculate the tumor cell fraction of the sample and therefore an unequivocal identification of the TCR clonotypes as neoplastic. Analysis of TCR sequences from 29 patients with MF stage I to IV proved the existence of multiple T-cell clones within the tumor cell fraction, with a considerable variation between patients and between lesions from the same patient (median, 11 clones; range, 2-80 clones/sample). We have also detected multiple neoplastic clones in the peripheral blood in all examined patients. Based on these findings, we propose that circulating neoplastic T-cell clones continuously replenish the lesions of MF, thus increasing their heterogeneity by a mechanism analogous to the consecutive tumor seeding. We hypothesize that circulating neoplastic clones might be a promising target for therapy and could be exploited as a potential biomarker in MF.

Original languageEnglish
JournalBlood
Volume134
Issue number18
Pages (from-to)1517-1527
Number of pages11
ISSN0006-4971
DOIs
Publication statusPublished - 31 Oct 2019

ID: 59268043