New insights in the pathogenesis of T-cell lymphomas

Lemonnier, François; Gaulard, Philippe; Leval, Laurence de

doi:10.1097/cco.0000000000000474

Cited by 31 publications

(24 citation statements)

References 80 publications

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“…This profile typically consists of epigenetic deregulation (various and often multiple inactivating TET2 +/-DNMT3A mutations, often occurring at early stages in haematopoietic progenitors, present in about 80% and 30-35% of the cases, respectively), 27,28 and second hit mutations with a more restricted distribution. 29 The latter include a hotspot RHOA G17V mutation encoding a dominant negative variant of the protein in up to 70% of cases, and other gain-offunction mutations targeting the TCR signalling pathway (PLCG1, CD28, FYN, PIK3 components, CARD11, etc.). [30][31][32] Mouse models have shown that RHOA G17V induces TFH specification, autoimmunity, and promotes lymphomagenesis in the presence of TET2 inactivation, indicating the synergistic effect of both mutations.…”

Section: Pathological Features Of Nodal-based Ptclsmentioning

confidence: 99%

Approach to nodal-based T-cell lymphomas

Leval

2020

Pathology

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Peripheral T-cell lymphomas (PTCLs) represent a heterogeneous group of uncommon malignancies derived from mature T cells and usually characterised by an aggressive clinical course. Their clinical presentation, localisation and pattern of dissemination are highly variable, but the majority of cases present as nodal diseases. The recently revised classification of lymphomas has incorporated many new molecular genetic data derived from gene expression profiling and next generation sequencing studies, which refine the definition and diagnostic criteria of several entities. Nevertheless, the distinction of PTCL from various reactive conditions, and the diagnosis of PTCL subtypes remains notably challenging. Here, an updated summary of the clinicopathological and molecular features of the most common nodal-based PTCLs (angioimmunoblastic T-cell lymphoma and other nodal lymphomas derived from follicular T helper cells, anaplastic large cell lymphomas and peripheral T-cell lymphoma, not otherwise specified) is presented. Practical recommendations in the diagnostic approach to nodal T-cell lymphoproliferations are presented, including indications for the appropriate use and interpretation of ancillary studies. Finally, we discuss commonly encountered diagnostic problems, including pitfalls and mimics in the differential diagnosis with various reactive conditions, and the criteria that allow proper identification of distinct PTCL entities.

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Section: Pathological Features Of Nodal-based Ptclsmentioning

confidence: 99%

Approach to nodal-based T-cell lymphomas

Leval

2020

Pathology

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“…Novel insights gleaned from high-throughput molecular and genomic profiling studies have contributed significantly to the understanding of peripheral T and NK cell lymphomas. The identification of a multistep oncogenic pathway which involves epigenetic deregulation related to TET2, DNMT3, or IDH2 mutations and mutations affecting genes related to TCR signaling pathway in nodal lymphomas of follicular helper T cell origin has been a major advancement [4]. Similarly, the uncovering of unique gene expression profiles with the identification of dysregulated signaling pathways [5–7], as well as the characterization of the mutational landscape via mutational profiling techniques in ENKTL, is providing new insights into the pathogenesis of this disease [8].…”

Section: Introductionmentioning

confidence: 99%

Molecular pathogenic pathways in extranodal NK/T cell lymphoma

et al. 2019

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Extranodal NK/T cell lymphoma, nasal type (ENKTL) is an aggressive malignancy with a dismal prognosis. Although l -asparaginase-based chemotherapy has resulted in improved response rates, relapse occurs in up to 50% of patients with disseminated disease. There is hence an urgent need for effective targeted therapy, especially for patients with relapsed or refractory disease. Novel insights gleaned from high-throughput molecular and genomic profiling studies in recent years have contributed significantly to the understanding of the molecular biology of ENKTL, which exemplifies many of the hallmarks of cancer. Deregulated pro-proliferative signaling pathways, such as the Janus-associated kinase/signal transducer and activator of transcription (JAK/STAT), platelet-derived growth factor (PDGF), Aurora kinase, MYC, and NF-κB, have been identified as potential therapeutic targets. The discovery of the non-canonical function of EZH2 as a pro-proliferative transcriptional co-activator has shed further light on the pathogenesis of ENKTL. Loss of key tumor suppressor genes located on chromosome 6q21 also plays an important role. The best-studied examples include PR domain zinc finger protein 1(PRDM1), protein tyrosine phosphatase kappa (PTPRK), and FOXO3. Promoter hypermethylation has been shown to result in the downregulation of other tumor suppressor genes in ENKTL, which may be potentially targeted through hypomethylating agents. Deregulation of apoptosis through p53 mutations and upregulation of the anti-apoptotic protein, survivin, may provide a further growth advantage to this tumor. A deranged DNA damage response as a result of the aberration of ataxia telangiectasia-related (ATR) kinases can lead to significant genomic instability and may contribute to chemoresistance of ENKTL. Recently, immune evasion has emerged as a critical pathway for survival in ENKTL and may be a consequence of HLA dysregulation or STAT3-driven upregulation of programmed cell death ligand 1 (PD-L1). Immunotherapy via inhibition of programmed cell death 1 (PD-1)/PD-L1 checkpoint signaling holds great promise as a novel therapeutic option. In this review, we present an overview of the key molecular and pathogenic pathways in ENKTL, organized using the framework of the “hallmarks of cancer” as described by Hanahan and Weinberg, with a focus on those with the greatest translational potential.

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“…To account for the complex genomic landscape of AITL, a multistep tumorigenesis model was proposed (41)(42)(43). The premalignant hematopoietic progenitor cells harboring mutations (e.g., TET2 and DNMT3A) are predisposed to the development of blood cancer, and the acquisition of second-hit mutations (e.g., RHOA G17V and IDH2 R172 ) in a subclone of TFH cells eventually leads to AITL.…”

Section: Multistep Tumorigenesis Modelmentioning

confidence: 99%

Genomics of Peripheral T-Cell Lymphoma and Its Implications for Personalized Medicine

et al. 2020

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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: RHOA G17V 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.

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New insights in the pathogenesis of T-cell lymphomas

Abstract: Understanding of PTCL pathogenesis has substantially improved, and oncogenic events have been identified. The current challenge is to mount efficient therapeutic strategies targeting these aberrations to improve patients' outcome.

Cited by 31 publications

References 80 publications

Approach to nodal-based T-cell lymphomas

Approach to nodal-based T-cell lymphomas

Molecular pathogenic pathways in extranodal NK/T cell lymphoma

Genomics of Peripheral T-Cell Lymphoma and Its Implications for Personalized Medicine

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