TY - JOUR

T1 - Single-cell heterogeneity in Sézary syndrome.

AU - Buus, Terkild Brink

AU - Willerslev-Olsen, Andreas

AU - Fredholm, Simon Mayland

AU - Blümel, Edda

AU - Nastasi, Claudia

AU - Gluud, Maria

AU - Hu, Tengpeng

AU - Lindahl, Lise M.

AU - Iversen, Lars

AU - Fogh, Hanne

AU - Gniadecki, Robert

AU - Litvinov, Ivan V.

AU - Persson, Jenny L.

AU - Bonefeld, Charlotte Menne

AU - Geisler, Carsten

AU - Christensen, Jan Pravsgaard

AU - Krejsgaard, Thorbjørn Frej

AU - Litman, Thomas

AU - Andersen, Anders Woetmann

AU - Ødum, Niels

PY - 2018

Y1 - 2018

N2 - 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.

AB - 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.

U2 - 10.1182/bloodadvances.2018022608

DO - 10.1182/bloodadvances.2018022608

M3 - Journal article

C2 - 30139925

VL - 2

SP - 2115

EP - 2126

JO - Blood advances

JF - Blood advances

SN - 2473-9529

IS - 16

ER -