Increased Chlormethine-Induced DNA Double-Stranded Breaks in Malignant T Cells from Mycosis Fungoides Skin Lesions

Yun-Tsan Chang; Desislava Ignatova; Wolfram Hoetzenecker; Steve Pascolo; Christina Fassnacht; Emmanuella Guenova

doi:10.1016/j.xjidi.2021.100069

Increased Chlormethine-Induced DNA Double-Stranded Breaks in Malignant T Cells from Mycosis Fungoides Skin Lesions

JID Innov. 2021 Nov 25;2(1):100069. doi: 10.1016/j.xjidi.2021.100069. eCollection 2022 Jan.

Authors

Yun-Tsan Chang^{1

2}, Desislava Ignatova¹, Wolfram Hoetzenecker³, Steve Pascolo¹, Christina Fassnacht¹, Emmanuella Guenova^{1

2}

Affiliations

¹ Department of Dermatology, University Hospital Zurich and Faculty of Medicine, University of Zurich, Zurich, Switzerland.
² Department of Dermatology, University Hospital Lausanne (CHUV), Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.
³ Department of Dermatology, Kepler University Hospital, Linz, Austria.

Abstract

Mycosis fungoides (MF) is a type of cutaneous T-cell lymphoma. Chlormethine (CL) is recommended as first-line therapy for MF, with a major purpose to kill tumor cells through DNA alkylation. To study the extent of treatment susceptibility and tumor specificity, we investigated the gene expression of different DNA repair pathways, DNA double-stranded breaks, and tumor cell proliferation of clonal TCR Vβ+ tumor cell populations in cutaneous T-cell lymphoma skin cells on direct exposure to CL. Healthy human T cells were less susceptible to CL exposure than two T-lymphoma cell lines, resulting in higher proportions of viable cells. Interestingly, in T cells from MF lesions, we observed a downregulation of several important DNA repair pathways, even complete silencing of RAD51AP1, FANC1, and BRCA2 involved in homologous recombination repair. In the presence of CL, the double-stranded DNA breaks in malignant MF skin T cells increased significantly as well as the expression of the apoptotic gene CASP3. These data point toward an important effect of targeting CL on MF skin tumor T cells, which support CL use as an early cutaneous lymphoma treatment and can be of synergistic use, especially beneficial in the setting of combination skin-directed therapies for cutaneous T-cell lymphoma.

Keywords: CL, chlormethine; CTCL, cutaneous T-cell lymphoma; DSB, double-stranded break; FBS, fetal bovine serum; HRR, homologous recombination repair; MF, mycosis fungoides; PMA, phorbol 12-myristate 13-acetate.