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Telomeric Repeat-containing RNA (TERRA) are long non-coding RNAs transcribed from telomeric DNA sequences from multiple chromosome ends. Major research efforts have been made to understand TERRA roles and functions in several physiological and pathological processes. We summarize herein available data regarding TERRA’s roles in human cells and we report the first investigation in cutaneous T-cells lymphomas (CTCL) using real-time PCR. Among the TERRA analysed, our data suggest a particular role for TERRA 16p downregulation and TERRA 11q upregulation in CTCL lymphomagenesis.

As a major cancer hallmark, there is a sustained interest in understanding the telomerase contribution to carcinogenesis in order to therapeutically target this enzyme. This is particularly relevant in primary cutaneous T-cell lymphomas (CTCL), a malignancy showing telomerase dysregulation with few investigative data available. In CTCL, we examined the mechanisms involved in telomerase transcriptional activation and activity regulation. We analyzed 94 CTCL patients from a Franco-Portuguese cohort, as well as 8 cell lines, in comparison to 101 healthy controls. Our results showed that not only polymorphisms (SNPs) located at the promoter of human telomerase reverse transcriptase (hTERT) gene (rs2735940 and rs2853672) but also an SNP located within the coding region (rs2853676) could influence CTCL occurrence. Furthermore, our results sustained that the post-transcriptional regulation of hTERT contributes to CTCL lymphomagenesis. Indeed, CTCL cells present a different pattern of hTERT spliced transcripts distribution from the controls, mostly marked by an increase in the hTERT β+ variants proportion. This increase seems to be associated with CTCL development and progression. Through hTERT splicing transcriptome modulation with shRNAs, we observed that the decrease in the α-β+ transcript induced a decrease in the cell proliferation and tumorigenic capacities of T-MF cells in vitro. Taken together, our data highlight the major role of post-transcriptional mechanisms regulating telomerase non canonical functions in CTCL and suggest a new potential role for the α-β+ hTERT transcript variant.

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) patients with MLL-SEPT6 fusion represent a small subset of AML. The uncommon MLL-SEPT6 rearrangement results from t(X;11) or other variants like ins(X;11), and it is usually associated with complex cytogenetic abnormalities. We herein report a case of AML-M5-infant with ins(X;11)(q24;q23q13) and MLL-SEPT6. The one-year-old boy presented with leukocytosis, anemia and thrombocytopenia. He had a favorable response to chemotherapy according to ELAM02protocol and is currently in complete remission. We here, highlight the occurrence of MLL-SEPT6 as the sole abnormality in a pediatric-AML-M5 case, discuss the prognostic implication of this genetic variant, while reviewing previously reported AML-MLL-SEPT6 cases.

Many biomarkers indicate prognosis in chronic lymphocytic leukemia; such as fluorescence in situ hybridization testing: 17p or 11q deletions have a worse prognosis than trisomy 12, 13q deletion or normal result, or the mutational status of the immunoglobulin heavy chain (IGHV): unmutated IGHV have a worse prognosis than mutated IGHV. Recently, many gene mutations ( TP53, NOTCH1 etc.,) have been linked to a worse prognosis. With the new era of high-throughput sequencing, it has become easier to study gene mutations and their implication in predicting prognosis. In this review, we aim to review all the studies that performed whole-exome sequencing or whole-genome sequencing on chronic lymphocytic leukemia cells and explore the implication of various genes in disease prognosis.

Background Cockayne Syndrome (CS) is a rare autosomal recessive disorder characterized by neurological and sensorial impairment, dwarfism, microcephaly and photosensitivity. CS is caused by mutations in ERCC6 (CSB) or ERCC8 (CSA) genes. Methods Three patients with CS were referred to the Medical Genetics Unit of Saint Joseph University. Sanger sequencing of both ERCC8 and ERCC6 genes was performed: ERCC8 was tested in all patients while ERCC6 in one of them. Results Sequencing led to the identification of three homozygous mutations, two in ERCC8 (p.Y322* and c.843 + 1G > C) and one in ERCC6 (p.R670W). All mutations were previously reported as pathogenic except for the c.843 + 1G > C splice site mutation in ERCC8 which is novel. Conclusions Molecular diagnosis was established in all patients included in our study. A genotype-phenotype correlation is discussed and a link, between mutations and some specific religious communities in Lebanon, is suggested. Electronic supplementary material The online version of this article (10.1186/s12881-018-0677-7) contains supplementary material, which is available to authorized users.

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.

Aim: We aimed to understand the biology of chronic lymphocytic leukemia (CLL) patients in Lebanon. Materials & methods: We applied conventional cytogenetic and FISH studies on Lebanese patients diagnosed with CLL and undergoing a watch and wait approach. Results: Our study disclosed 53.6% of patients with aberrant karyotypes among which 26.7% were complex karyotypes. Genetic aberrations included del(13q14) 46.4%, 14q32 translocation in 25%, trisomy 12 in 14.3%, del(17p13) and del(11q22) in 7.1% each. The deletion of 6q21/6q23 was not found in any of our patients. Conclusion: The higher prevalence of del(13q14) as a sole abnormality could be the primary event in inducing CLL. The del(17p13) and del(11q22) followed as potential drivers for progression in CLL patients with a watch and wait approach.

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.