Exploring hTERT promoter methylation in cutaneous T-cell lymphomas.

Alain Chebly,Eliane Chouery,Jean‐Marie Peloponese,Edith Chevret,Yamina Idrissi,Chantal Farra,Evelyne Segal‐Bendirdjian,Jacky Ferrer,Joana Ropio,Floriane Cherrier,Anne Pham‐Ledard,Sandrine Poglio,Jean‐Philippe Merlio,Marie Beylot‐Barry,Martina Prochazkova‐Carlotti,Roland Tomb

doi:10.1002/1878-0261.12946

Abstract

Cutaneous T‐cell lymphomas (CTCLs) are telomerase‐positive tumors expressing hTERT, although neither gene rearrangement/amplification nor promoter hotspot mutations could explain the hTERT re‐expression. As the hTERT promoter is rich in CpG, we investigated the contribution of epigenetic mechanisms in its re‐expression. We analyzed hTERT promoter methylation status in CTCL cells compared with healthy cells. Gene‐specific methylation analyses revealed a common methylation pattern exclusively in tumor cells. This methylation pattern encompassed a hypermethylated distal region from −650 to −150 bp and a hypomethylated proximal region from −150 to +150 bp. Interestingly, the hypermethylated region matches with the recently named TERT hypermethylated oncogenic region (THOR). THOR has been associated with telomerase reactivation in many cancers, but it has so far not been reported in cutaneous lymphomas. Additionally, we assessed the effect of THOR on two histone deacetylase inhibitors (HDACi), romidepsin and vorinostat, both approved for CTCL treatment and a DNA methyltransferase inhibitor (DNMTi) 5‐azacytidine, unapproved for CTCL. Contrary to our expectations, the findings reported herein revealed that THOR methylation is relatively stable under these epigenetic drugs' pressure, whereas these drugs reduced the hTERT gene expression.

Highlights

Cutaneous T-cell lymphomas (CTCLs) encompass a heterogeneous group of rare T lymphoproliferative disorders, characterized by clonal proliferation of malignant T cells involving the skin as a primary site
A common human telomerase reverse transcriptase gene (hTERT) promoter methylation pattern in CTCL cell lines and in Sezary syndrome (SS) patient-derived cells (PDCs) was revealed by locusspecific bisulfite sequencing (Fig. 2)
Since two histone deacetylases inhibitors (HDACi) are approved for CTCL treatment, without clear molecular investigations, we studied the effect of these two drugs focusing on hTERT expression in SS cells. hTERT expression decreased significantly (P < 0.001) in SS PDCs 1, 2, and 3 after romidepsin and vorinostat treatments (Fig. 6A)

Summary

Introduction

Cutaneous T-cell lymphomas (CTCLs) encompass a heterogeneous group of rare T lymphoproliferative disorders, characterized by clonal proliferation of malignant T cells involving the skin as a primary site. They include cutaneous anaplastic large cell lymphoma (CALCL), mycosis fungoıdes (MF), and Sezary syndrome (SS) [1]. Treatment of MF/SS can be very challenging, especially in the advanced stages of the disease. The choice of the therapeutic agent is stage-dependent, including drugs such as bexarotene, methotrexate, interferon-alpha, and histone deacetylases inhibitors (HDACi) or the recently introduced monoclonal antibodies such as mogamulizumab, brentuximab vedotin, or IPH4102. While chemotherapies only allow short-lived responses, allogenic stem cell transplantation remains the only curative option [3,4]

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Discussion

Conclusion