Sézary syndrome (SS) is an aggressive, leukemic cutaneous T-cell lymphoma variant. Molecular pathogenesis of SS is still unclear despite many studies on genetic alterations, gene expression and epigenetic regulations. Through whole genome and transcriptome next generation sequencing nine Sézary syndrome patients were analyzed in terms of copy number variations and rearrangements affecting gene expression. Recurrent copy number variations were detected within 8q (MYC, TOX), 17p (TP53, NCOR1), 10q (PTEN, FAS), 2p (DNMT3A), 11q (USP28), 9p (CAAP1), but no recurrent rearrangements were identified. However, expression of five genes involved in rearrangements (TMEM244, EHD1, MTMR2, RNF123 and TOX) was altered in all patients. Fifteen rearrangements detected in Sézary syndrome patients and SeAx resulted in an expression of new fusion transcripts, nine of them were in frame (EHD1-CAPN12, TMEM66-BAIAP2, MBD4-PTPRC, PTPRC-CPN2, MYB-MBNL1, TFG-GPR128, MAP4K3-FIGLA, DCP1A-CCL27, MBNL1-KIAA2018) and five resulted in ectopic expression of fragments of genes not expressed in normal T-cells (BAIAP2, CPN2, GPR128, CAPN12, FIGLA). Our results not only underscored the genomic complexity of the Sézary cancer cell genome but also showed an unpreceded large variety of novel gene rearrangements resulting in fusions transcripts and ectopically expressed genes.

T cell lymphomas (TCL) comprise a heterogeneous group of non-Hodgkin lymphomas (NHL) that often present at an advanced stage at the time of diagnosis and that most commonly have an aggressive clinical course. Treatment in the front-line setting is most often cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP-like regimens, which are effective in B cell lymphomas, but in TCL are associated with a high failure rate and frequent relapses. Furthermore, in contrast to B cell NHL, in which substantial clinical progress has been made with the introduction of monoclonal antibodies, no comparable advances have been seen in TCL. To change this situation and improve the prognosis in TCL, new gene-targeted therapies must be developed. This is now possible due to enormous progress that has been made in the last years in the understanding of the biology and molecular pathogenesis of TCL, which enables the implementation of the research findings in clinical practice. In this review, we present new therapies and current clinical and preclinical trials on targeted treatments for TCL using histone deacetylase inhibitors (HDACi), antibodies, chimeric antigen receptor T cells (CARTs), phosphatidylinositol 3-kinase inhibitors (PI3Ki), anaplastic lymphoma kinase inhibitors (ALKi), and antibiotics, used alone or in combinations. The recent clinical success of ALKi and conjugated anti-CD30 antibody (brentuximab-vedotin) suggests that novel therapies for TCL can significantly improve outcomes when properly targeted.

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Sezary syndrome (SS) is a rare form of cutaneous T-cell lymphoma characterized by erythroderma and the presence of Sezary cells in the skin, lymph nodes, and peripheral blood. Over the past few decades, cytogenetic and molecular cytogenetic findings have revealed many genetic alterations in patients with SS. The most frequent genetic lesions include monosomy 10, losses of 10q and 17p, gains of 8q24 and 17q, and diverse structural alterations involving these regions. Expression patterns in regions of genomic imbalance show that a large number of genes in SS are deregulated, and this might have a causative role in oncogenesis. Overall, chromosomal instability is characteristic of this lymphoma and related to a poor prognosis, but no specific abnormalities that may be directly involved in development of the disease have yet been found.

Several genome-wide association studies (GWASs), have identified that FAM13A and IREB2 loci are associated with lung cancer, but the mechanisms by which these genes contribute to lung diseases susceptibility, especially in hypoxia context, are unknown. Hypoxia has been identified as a major negative factor for tumor progression in clinical observation. It has been suggested, that lower oxygen tension, may modulate the IREB2 and FAM13A activity. However, the role of these genes in hypoxia response has not been explained. To precise the role of these genes in hypoxia response, we analyzed the FAM13A and IREB2 expression, in lung cancer cells in vitro and lung cancer tissue fragments cultured ex vivo.Three cell lines: non-small cell lung cancer (A549, CORL-105), human lung fibroblasts (HL) and 37 lung cancer tissue fragments were analyzed. The expression of IREB2, FAM13A and HIF1α after sustained 72 hours of hypoxia versus normal oxygen concentration were analyzed by TaqMan® Gene Expression Assays and Western Blot.The expression of FAM13A was significantly up-regulated by hypoxia in two lung cancer cell lines (A549, CORL-105, P<0.001), both at the level of protein and mRNA, and in lung cancer tissue fragments (P=0.0004). The IREB2 was down-regulated after hypoxia in A549 cancer cells (P<0.001).Conclusions: We found that FAM13A overexpression in human lung cancer cell lines overlapped with hypoxia effect on lung cancer tissues. FAM13A is strongly induced by hypoxia and may be identified as a novel hypoxia-induced gene in non-small cell lung cancer.

Cutaneous T-cell lymphomas (CTCLs) represent a large, heterogeneous group of non-Hodgkin lymphomas that primarily affect the skin. Among multiple CTCL variants, the most prevalent types are mycosis fungoides (MF) and Sézary syndrome (SS). In the past decade, the molecular genetics of CTCL have been the target of intense study, increasing the knowledge of CTCL genomic alterations, discovering novel biomarkers, and potential targets for patient-specific therapy. However, the detailed pathogenesis of CTCL development still needs to be discovered. This review aims to summarize the novel insights into molecular heterogeneity of malignant cells using high-throughput technologies, such as RNA sequencing and single-cell RNA sequencing, which might be useful to identify tumour-specific molecular signatures and, therefore, offer guidance for therapy, diagnosis, and prognosis of CTCL.

Sézary syndrome (SS) is an aggressive form of cutaneous T‐cell lymphoma (CTCL) characterized by the presence of circulating malignant CD4+ T cells (Sézary cells) with many complex changes in the genome, transcriptome and epigenome. Epigenetic dysregulation seems to have an important role in the development and progression of SS as it was shown that SS cells are characterized by widespread changes in DNA methylation. In this study, we show that the transmembrane protein coding gene TMEM244 is ectopically expressed in all SS patients and SS‐derived cell lines and, to a lower extent, in mycosis fungoides and in a fraction of T‐cell lymphomas, but not in B‐cell malignancies and mononuclear cells of healthy individuals. We show that in patient samples and in the T‐cell lines TMEM244 expression is negatively correlated with the methylation level of its promoter. Furthermore, we demonstrate that TMEM244 expression can be activated in vitro by the CRISPR‐dCas9–induced specific demethylation of TMEM244 promoter region. Since both, TMEM244 expression and its promoter demethylation, are not detected in normal lymphoid cells, they can be potentially used as markers in Sézary syndrome and some other T‐cell lymphomas.

The 6q23-27 region, recurrently deleted in Sézary syndrome (SS), was characterized at the molecular level in 13 SS patients and SS cell line SeAx. Using fine-tiling comparative genomic hybridization, deletions within the 6q23-27 region were detected in half of the samples (six patients and SeAx). All samples with deletions were further analyzed by ligation-mediated PCR. In addition, in one patient sample and in SeAx, paired-end next-generation sequencing was performed on the HiSeq2000 Illumina platform. Using those techniques, 23 rearrangements associated with the deletions were identified. The majority of rearrangements showed enormous complexity and diversity, including eight inversions, three transpositions, and four translocations (with chromosomes 3, 17, 10, and 12). Fifteen genes were disrupted by those rearrangements, the MYB proto-oncogene three times and the interleukin-22 receptor subunit alpha-2 gene (IL22RA2) twice. All three patients with MYB alterations showed low MYB expression, whereas seven of the remaining patients showed overexpression. Most patients overexpressing MYB also presented increased expression of MYC, HSPA8, and BCL2. Five gene fusions were identified, of which two, CCDC28A-IL22RA2 and AIG1-GOSR1, both in SeAx, were in the same orientation and were expressed at the messenger RNA level.