Genetic Landscape of Peripheral T-Cell Lymphoma

Abstract

Peripheral T-Cell lymphoma (PTCL) comprises a heterogenous group of uncommon lymphomas derived from mature, post-thymic or “peripheral” T- and natural killer cells. The World Health Organization (WHO) emphasizes a multiparameter approach in the diagnosis and subclassification of these neoplasms, integrating clinical, morphologic, immunophenotypic, and genetic features into the final diagnosis. Clinical presentation is particularly important due to histologic, immunophenotypic and genetic variations within established subtypes, and no convenient immunophenotypic marker of monoclonality exists. In recent years, widespread use of gene expression profiling and next-generation sequencing (NGS) techniques have contributed to an improved understanding of the pathobiology in PTCLs, and these have been incorporated into the 2016 revised WHO classification of mature T- and NK-cell neoplasms which now encompasses nearly 30 distinct entities. This review discusses the genetic landscape of PTCL and its role in subclassification, prognosis, and potential targeted therapy. In addition to discussing T-Cell lymphoma subtypes with relatively well-defined or relevant genetic aberrancies, special attention is given to genetic advances in T-Cell lymphomas of T follicular helper cell (TFH) origin, highlighting genetic overlaps between angioimmunoblastic T-Cell lymphoma (AITL), follicular T-Cell lymphoma, and nodal peripheral T-Cell lymphoma with a TFH phenotype. Furthermore, genetic drivers will be discussed for ALK-negative anaplastic large cell lymphomas and their role in differentiating these from CD30+ peripheral T-Cell lymphoma, not otherwise specified (NOS) and primary cutaneous anaplastic large cell lymphoma. Lastly, a closer look is given to genetic pathways in peripheral T-Cell lymphoma, NOS, which may guide in teasing out more specific entities in a group of T-Cell lymphomas that represents the most common subcategory and is sometimes referred to as a “wastebasket” category.

The fusion oncogene VAV1‐MYO1F triggers aberrant T‐cell receptor signaling in vivo and drives peripheral T‐cell lymphoma in mice

“…Moreover, determining whether the activation profile and aberrant signaling we observe is mediated entirely from within the cell through VAV1‐MYO1F expression, or if the cell is dependent on MHC‐II‐mediated TCR signaling, would shed light on the mechanism of VAV1‐MYO1F‐mediated ‐T‐cell NHL development. Lastly, these data also show that VAV1‐MYO1F expression enforces a pathological skewing of T‐cell differentiation toward a Tfh like mixed phenotype, with dual GATA3 and T‐bet expression, which is detected in human PTCL‐NOS lymphomas [14–16].…”

Adult-Onset Systemic Chronic Active Epstein - Barr virus Disease: A Case Report Highlighting Unique Immunophenotype and Novel Molecular Insights in the Context of Chronic HBV Hepatitis

“…Among four detected mutational changes in this case only CREBBP is relatively uncommonly seen in T cell lymphomas. (24) The identification of novel TP73, SPEN and PLCG2 mutations adds a layer of complexity to the understanding of the molecular mechanisms underlying EBV-associated lymphoproliferative disorders. TP73 mutations, although rare in cancer, have been implicated in HBV-associated B-cell lymphomas, suggesting a potential link between HBV infection and T-cell lymphomagenesis.…”

Rational Targets of Therapy in Extranodal NK/T-Cell Lymphoma

“…MLL genes are also commonly mutated in up to 19% of ENKTL cases, specifically MLL2 (KMT2D) and MLL3 (KMT2C), which are involved in histone methylation and may be tumor suppressors in B-cell lymphomas, although the role of these epigenetic regulators specifically in the tumorigenesis of ENKTL is unknown [19,28,32,43]. Other commonly mutated epigenetic regulatory genes in ENKTL include TET1/TET2, EP200, ASXL3, CREBBP, and ARID1A, with yet unknown functions in ENKTL biology [19,32,44].…”