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.

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.