Abstract
The pathomechanism of mycosis fungoides (MF), the most common type of primary cutaneous T-cell lymphomas (CTCLs) and a malignancy of non-recirculating, skin-resident T-cells, is unknown albeit underlying viral infections have been sought for. Human endogenous retroviruses (HERVs) are ancient retroviral sequences in the human genome and their transcription is often deregulated in cancers. We explored the transcriptional activity of HERV sequences in a total of 34 samples comprising MF and psoriasis skin lesions, as well as corresponding non-malignant skin using a retrovirus-specific microarray and quantitative RT-PCR. To identify active HERV-W loci, we cloned the HERV-W specific RT-PCR products, sequenced the cDNA clones and assigned the sequences to HERV-W loci. Finally, we used immunohistochemistry on MF patient and non-malignant inflammatory skin samples to confirm specific HERV-encoded protein expression. Firstly, a distinct, skin-specific transcription profile consisting of five constitutively active HERV groups was established. Although individual variability was common, HERV-W showed significantly increased transcription in MF lesions compared to clinically intact skin from the same patient. Predominantly transcribed HERV-W loci were found to be located in chromosomes 6q21 and 7q21.2, chromosomal regions typically altered in CTCL. Surprisingly, we also found the expression of 7q21.2/ERVWE1-encoded Syncytin-1 (Env) protein in MF biopsies and expression of Syncytin-1 was seen in malignant lymphocytes, especially in the epidermotropic ones, in 15 of 30 cases studied. Most importantly, no Syncytin-1 expression was detected in inflammatory dermatosis (Lichen ruber planus) with skin-homing, non-malignant T lymphocytes. The expression of ERVWE1 mRNA was further confirmed in 3/7 MF lesions analyzed. Our observations strengthen the association between activated HERVs and cancer. The study offers a new perspective into the pathogenesis of CTCL since we demonstrate that differences in HERV-W transcription levels between lesional MF and non-malignant skin are significant, and that ERVWE1-encoded Syncytin-1 is expressed in MF lymphoma cells.
Highlights
cutaneous T-cell lymphomas (CTCLs) represent a group of heterogenous non-Hodgkin lymphomas arising mostly from CD4+ T-cells
A retrovirus-specific microarray (RetroArray), previously described in detail [60], was used to define a distinct skinspecific Human endogenous retroviruses (HERVs) transcription profile [60]; see Methods). In this semi-quantitative analysis, seven constitutively transcribed HERV taxa derived from five HERV groups (HERV-E, HERV-F, HERV-W, ERV9, HERV-K (HML-4) were detected in at least 90% of healthy skin samples (Figure 1). This HERV core transcription pattern was compared with the HERV core signature of other human tissues such as brain, mamma, urothelium, and kidney
For the first time, the transcription of HERVs in mycosis fungoides (MF), the most common form of CTCL
Summary
CTCLs represent a group of heterogenous non-Hodgkin lymphomas arising mostly from CD4+ T-cells. The clinical behavior of these lymphomas varies from a non-progressive early mycosis fungoides (MF) to rapidly progressing leukaemic Sézary syndrome (SS) [1,2]. The most common type of CTCL, MF represents a malignancy of skin-homing T-cells, i.e. sessile, non-recirculating, skin-resident effector memory T-cells (TEM) [3]. Chromosome aberrations are diverse including numerical (DNA copy number changes) as well as structural (deletions, translocations, inversions) alterations. Altered chromosomes include chromosomes 1, 2, 3, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 17, and 19, but almost any chromosome can be involved [5,6,7,8,9,10,11,12]
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