Résumé
Cutaneous T-cell lymphomas (CTCL) encompass a heterogeneous group of T lymphoproliferative disorders. We have previously shown that CTCL are telomerase positive tumors expressing hTERT in which neither amplification nor promoter hotspot mutations could explain the hTERT re-expression. Since the hTERT promoter region is rich in CpG islands, we investigated the contribution of DNA methylation in hTERT expression. We compared hTERT promoter methylation status in CTCL cell lines, Sézary syndrome (SS) patient-derived cells, fresh SS patient cells, and in normal CD4+ and CD34+ cells from healthy donors. Bisulfite Sanger sequencing revealed in tumor cells a common methylation pattern encompassing a hyper- methylated distal region from -650bp to -150bp and a hypomethylated proximal region from -150bp to +150bp (relatively to the transcription start site). Interestingly, the identified hypermethylated region in CTCL cells matches with the recently described TERT Hypermethylated Onco- genic Region (THOR) reported to be associated with telomerase reactivation in many cancers, but so far not studied in lymphomas. Moreover, we assessed the effect on THOR methylation of two histone deacetylase inhibitors (HDACi), romidepsin and vorinostat, both approved for the treatment of CTCL patients. Overall, our results show the contribution of THOR hypermethylation in hTERT re-expression in neoplastic CTCL cells and provide new insights into the effects of epigenetic drugs (HDACi) on THOR methylation for the first time in lymphomas.