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Single-cell heterogeneity in Sézary syndrome

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  • Terkild Brink Buus
  • Andreas Willerslev-Olsen
  • Simon Fredholm
  • Edda Blümel
  • Claudia Nastasi
  • Maria Gluud
  • Tengpeng Hu
  • Lise M Lindahl
  • Lars Iversen
  • Hanne Fogh
  • Robert Gniadecki
  • Ivan V Litvinov
  • Jenny L Persson
  • Charlotte Menné Bonefeld
  • Carsten Geisler
  • Jan Pravsgaard Christensen
  • Thorbjørn Krejsgaard
  • Thomas Litman
  • Anders Woetmann
  • Niels Ødum
Vis graf over relationer

Sézary syndrome (SS) is an aggressive leukemic variant of cutaneous T-cell lymphoma (CTCL) with a median life expectancy of less than 4 years. Although initial treatment responses are often good, the vast majority of patients with SS fail to respond to ongoing therapy. We hypothesize that malignant T cells are highly heterogeneous and harbor subpopulations of SS cells that are both sensitive and resistant to treatment. Here, we investigate the presence of single-cell heterogeneity and resistance to histone deacetylase inhibitors (HDACi) within primary malignant T cells from patients with SS. Using single-cell RNA sequencing and flow cytometry, we find that malignant T cells from all investigated patients with SS display a high degree of single-cell heterogeneity at both the mRNA and protein levels. We show that this heterogeneity divides the malignant cells into distinct subpopulations that can be isolated by their expression of different surface antigens. Finally, we show that treatment with HDACi (suberanilohydroxamic acid and romidepsin) selectively eliminates some subpopulations while leaving other subpopulations largely unaffected. In conclusion, we show that patients with SS display a high degree of single-cell heterogeneity within the malignant T-cell population, and that distinct subpopulations of malignant T cells carry HDACi resistance. Our data point to the importance of understanding the heterogeneous nature of malignant SS cells in each individual patient to design combinational and new therapies to counter drug resistance and treatment failure.

OriginalsprogEngelsk
TidsskriftBlood advances
Vol/bind2
Udgave nummer16
Sider (fra-til)2115-2126
Antal sider12
ISSN2473-9529
DOI
StatusUdgivet - 28 aug. 2018

ID: 56203233