Abstract
Peripheral T-cell lymphoma (PTCL) is a rare, heterogenous group of mature T-cell neoplasms that comprise 10–15% of non-Hodgkin lymphoma cases in the United States. All subtypes of PTCL, except for ALK+ anaplastic T-cell lymphoma, are associated with poor prognosis, with median overall survival (OS) rates of 1–3 years. The diagnosis of PTCL is mainly based on clinical presentation, morphologic features, and immunophenotypes. Recent advances in genome sequencing and gene expression profiling have given new insights into the pathogenesis and molecular biology of PTCL. An enhanced understanding of its genomic landscape holds the promise of refining the diagnosis, prognosis, and management of PTCL. In this review, we examine recently discovered genetic abnormalities identified by molecular profiling in 3 of the most common types of PTCL: RHOAG17V and epigenetic regulator mutations in angioimmunoblastic T-cell lymphoma, ALK expression and JAK/STAT3 pathway mutations in anaplastic T-cell lymphoma, and T-follicular helper phenotype and GATA3/TBX21 expression in PTCL-not otherwise specified. We also discuss the implications of these abnormalities for clinical practice, new/potential targeted therapies, and the role of personalized medicine in the management of PTCL.
Highlights
Peripheral T-cell lymphoma (PTCL) is a rare and heterogeneous group of mature T-cell neoplasms, comprising 10–15% of all cases of non-Hodgkin lymphoma cases in the United States [1], with at least 29 subtypes recognized by the revised 2016 World Health Organization classification of lymphoid neoplasms [2]
Mutations in TET2 and DNMT3A are associated with hypermethylation and dysregulated gene expression [11, 32], and the IDH2R172 mutant confers neo-enzymatic activity, producing oncometabolite D-2 hydroxyglutarate (D-2-HG)
The high cooccurrence of TET2 and IDH2R172 mutations in angioimmunoblastic T-cell lymphoma (AITL) suggests a synergistic effect, by which these genes upregulate follicular T helper–associated genes and downregulate genes associated with TH1, TH2, and TH17 cells [7, 19]
Summary
Peripheral T-cell lymphoma (PTCL) is a rare and heterogeneous group of mature T-cell neoplasms, comprising 10–15% of all cases of non-Hodgkin lymphoma cases in the United States [1], with at least 29 subtypes recognized by the revised 2016 World Health Organization classification of lymphoid neoplasms [2]. We focus on the recently discovered somatic genetic abnormalities of and emerging therapies for 3 of the most common PTCL subtypes: angioimmunoblastic T-cell lymphoma (AITL), anaplastic large cell lymphoma (ALCL), and PTCL-not otherwise specified (PTCL-NOS) (Supplementary Table 1). ANGIOIMMUNOBLASTIC T-CELL LYMPHOMA AND OTHER NODAL LYMPHOMAS OF FOLLICULAR T HELPER CELL ORIGIN. Recent advances in next-generation sequencing have led to the discovery of recurrent mutations in AITL. The most frequently reported somatic mutations include alterations in epigenetic regulators; ras homolog family member A (RHOA); and T-cell receptor (TCR) signaling pathway molecules (Table 1)
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