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Sezary syndrome (SS) is an aggressive leukemic variant of cutaneous T-cell lymphomas (CTCL) for which current available treatments do not provide long-term responses. Two epigenetic-modulating agents belonging to the family of histone deacetylase inhibitors (HDACi), vorinostat and romidepsin are FDA approved for advanced stage CTCL. However, the rationale for using such therapies in SS and their biological impact are not well defined. The majority of cancer cells achieve proliferative immortality by activating or upregulating the normally silent human Telomerase Reverse Transcriptase (hTERT) gene. Sezary cells do not escape to this phenomenon. 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 to healthy cells. Nine CTCL cell lines including, five SS cell lines were experimentally investigated (HuT78, the unique commercial SS cell line and four newly developed SS cell lines from our laboratory (PMID: 33106625). Gene-specific methylation analyses revealed a common promotor hypermethylation pattern exclusively observed in tumor cells. We explored hTERT promoter methylation status under the pressure of a demethylating agent approved for the treatment of several hematological disorders (5-azacytidine) by comparison with clinically approved HDACi (romidespin and vorinostat). Surprisingly, romidespin, vorinostat or 5-azacytidine could each reduce hTERT expression level without altering the methylation status of hTERT promoter. To go further, we analyzed the functional effect of the aforementioned epidrugs on the clonogenic capacities of Sezary cells using the soft agar assay. Our data revealed that, besides hTERT downregulation, epidrugs reduced the proliferative and the tumor formation capacities in Sezary cells in vitro. Our first report on hTERT promotor methylation status in CTCL suggests that hTERT promotor methylation status is a hallmark of neoplastic CTCL cells. Our results also provide evidence for functional consequences of epidrugs treatments on tumor formation capacities in Sezary cells in vitro. Indeed, the present investigation states that Sezary cells’ clonogenic capacity correlates well with hTERT expression level under epigenetic drugs pressure. The present findings represent a step forward towards a better understanding of the relationship between targeting epigenetic modifiers in a cell-context–dependent manner and the response generated at the cellular levels.

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.

Acute myeloid leukemia (AML) is characterized by chromosomal abnormalities affecting both prognosis and course of treatment. While most AML patients have well described chromosomal aberrations, around 10% present with rare chromosomal abnormalities. We herein, report a rare balanced translocation t(12;19)(q13;q13) in a 66-year old M5-AML patient identified by Conventional cytogenetic analysis and confirmed by SNP array. We suggest that t(12;19) as a sole chromosomal abnormality could be associated with a poor prognosis. Further studies are needed to understand the molecular basis of this translocation in AML.

Lymphomas represent a heterogeneous group of cancers characterized by clonal lymphoproliferation. Over the past decades, frequent epigenetic dysregulations have been identified in hematologic malignancies including lymphomas. Many of these impairments occur in genes with established roles and well-known functions in the regulation and maintenance of the epigenome. In hematopoietic cells, these dysfunctions can result in abnormal DNA methylation, erroneous chromatin state and/or altered miRNA expression, affecting many different cellular functions. Nowadays, it is evident that epigenetic dysregulations in lymphoid neoplasms are mainly caused by genetic alterations in genes encoding for enzymes responsible for histone or chromatin modifications. We summarize herein the recent epigenetic modifiers findings in lymphomas. We focus also on the most commonly mutated epigenetic regulators and emphasize on actual epigenetic therapies.

Chronic lymphocytic leukemia (CLL) is the most common type of adult leukemia. Chromosomal abnormalities are reported to play important roles in CLL pathogenesis and evolution, including deletions of 11q, 13q, 17p, and trisomy12, that are frequently observed and have a known prognostic value. Furthermore, the mutational status of the IGHV gene was reported as an independent prognostic marker in CLL impacting the choice of therapy. We herein, report an unusual presentation of a Lebanese CLL patient with two cytogenetic abnormalities: trisomy 12 and t(14;18)(q32;q21), along with an unmutated IGHV, displaying a favorable response to ibrutinib with a maintained complete remission.