Overlap at the molecular and immunohistochemical levels between angioimmunoblastic T-cell lymphoma and a subgroup of peripheral T-cell lymphomas without specific morphological features

Manso, Rebeca; González-Rincón, Julia; Rodriguez‐Justo, Manuel; Roncador, Giovanna; Gómez, Sagrario; Sánchez‐Beato, Margarita; Piris, Miguel Á.; Rodríguez‐Pinilla, Socorro María

doi:10.18632/oncotarget.24592

Cited by 29 publications

(27 citation statements)

References 49 publications

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“…The mutation profile of PTCL-T FH identified mutations in TET2, DNMT3A, and RHOA, which are also common in AITL; however, we did not observe IDH2 R172 mutations, consistent with previous reports. 9,48 Although the number of PTCL-T FH cases studied to date is small, the data suggest that PTCL-T FH may be a genetically distinct entity from AITL.…”

Section: Discussionmentioning

confidence: 99%

Genetic drivers of oncogenic pathways in molecular subgroups of peripheral T-cell lymphoma

Heavican

Bouska

et al. 2019

Blood

207

243

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Peripheral T-cell lymphoma (PTCL) is a group of complex clinicopathological entities, often associated with an aggressive clinical course. Angioimmunoblastic T-cell lymphoma (AITL) and PTCL-not otherwise specified (PTCL-NOS) are the 2 most frequent categories, accounting for >50% of PTCLs. Gene expression profiling (GEP) defined molecular signatures for AITL and delineated biological and prognostic subgroups within PTCL-NOS (PTCL-GATA3 and PTCL-TBX21). Genomic copy number (CN) analysis and targeted sequencing of these molecular subgroups revealed unique CN abnormalities (CNAs) and oncogenic pathways, indicating distinct oncogenic evolution. PTCL-GATA3 exhibited greater genomic complexity that was characterized by frequent loss or mutation of tumor suppressor genes targeting the CDKN2A/B-TP53 axis and PTEN-PI3K pathways. Co-occurring gains/amplifications of STAT3 and MYC occurred in PTCL-GATA3. Several CNAs, in particular loss of CDKN2A, exhibited prognostic significance in PTCL-NOS as a single entity and in the PTCL-GATA3 subgroup. The PTCL-TBX21 subgroup had fewer CNAs, primarily targeting cytotoxic effector genes, and was enriched in mutations of genes regulating DNA methylation. CNAs affecting metabolic processes regulating RNA/protein degradation and T-cell receptor signaling were common in both subgroups. AITL showed lower genomic complexity compared with other PTCL entities, with frequent co-occurring gains of chromosome 5 (chr5) and chr21 that were significantly associated with IDH2R172 mutation. CN losses were enriched in genes regulating PI3K–AKT–mTOR signaling in cases without IDH2 mutation. Overall, we demonstrated that novel GEP-defined PTCL subgroups likely evolve by distinct genetic pathways and provided biological rationale for therapies that may be investigated in future clinical trials.

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Section: Discussionmentioning

confidence: 99%

Genetic drivers of oncogenic pathways in molecular subgroups of peripheral T-cell lymphoma

Heavican

Bouska

et al. 2019

Blood

207

243

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“…Both genetic and antibody-based approaches were used to demonstrate that PD-1, perhaps not surprisingly, is a dominant checkpoint in this model 16. The extent to which these findings are generalisable to human PTCL remains uncertain, however, as PD-1 expression is prevalent in many PTCL, particularly those that are Tfh derived 11 20 21 33 38 39. Furthermore, PD-1 impairs TCR signalling and proliferation in large part by impairing PI3K/Akt signalling in a PTEN-dependent manner.…”

Section: Discussionmentioning

confidence: 92%

“…For example, inducible T cell costimulatory (ICOS) is highly expressed on follicular helper T (Tfh) cells and is required for their differentiation and maintenance 30–32. Not surprisingly then, ICOS is expressed by Tfh-derived PTCL and collaborates with the genetic landscape to promote their growth and survival 7 33. Despite the emerging role of costimulatory receptors (‘signal 2’) in T cell lymphomagenesis, the potential role of alternative, and inhibitory, CD28 family members in T cell lymphomagenesis has been little studied, at least until recently.…”

Section: Discussionmentioning

confidence: 99%

“…The PD-1 cytoplasmic tail, by recruiting the protein tyrosine phosphatase SHP2, inhibits proximal TCR signalling,34 leading to increased PTEN phosphatase activity and potent inhibition of PI3K-Akt signalling 35–37. PD-1 is highly expressed in the majority of most PTCL, including PTCL, NOS and Tfh-derived PTCL and other T cell lymphomas 11 20 21 33 38 39. Its potential role as a tumour suppressor in T cell lymphomas was investigated using mice that transgenically express a novel ITK–SYK fusion protein.…”

Section: Discussionmentioning

confidence: 99%

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Expression of the checkpoint receptors LAG-3, TIM-3 and VISTA in peripheral T cell lymphomas

2019

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AimsPeripheral T cell lymphomas represent approximately 10%–15% of non-Hodgkin lymphomas and are characterised by an aggressive clinical courses and poor outcomes. Ligands provided by constituents of the tumour microenvironment engage receptors expressed by malignant T cells, promoting tumour growth and chemotherapy resistance. In addition to stimulatory receptors that promote the growth and survival of malignant T cells, recent studies suggest that homologous inhibitory receptors may have an opposing effect and function as tumour suppressors. For example, recent data suggest that programmed cell death 1 blockade may lead to increased lymphoma growth. Therefore, the identification of alternative checkpoint receptors in T cell lymphoproliferative neoplasms is an important and clinically relevant question.MethodsThe checkpoint receptors T cell immunoglobulin-3 (TIM-3), V-domain Ig-containing suppressor of T cell activation (VISTA) and lymphocyte-activation gene 3 (LAG-3) play fundamental roles in peripheral tolerance, and their ligands are exploited by many solid tumours to evade host immunity. However, their expression in T cell lymphoproliferative neoplasms has not been evaluated. In this study, we evaluated the expression of TIM-3, VISTA and LAG-3 in a cohort of peripheral T cell lymphomas cases by immunohistochemistry and flow cytometric analysis.ResultsOur results demonstrate that TIM-3, VISTA and LAG-3 expression is rarely identified within a large cohort of T cell lymphomas and its tumour microenvironment.ConclusionsOur data suggest that immune-regulatory roles for TIM-3, VISTA and LAG-3 may be predominant in lymphomas subsets different than the ones analysed in the current study. However, a potential role for these checkpoint receptors as tumour suppressors in T cell lymphomas remains to be elucidated.

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“…While other mutations in RHOA were reported, the change leading to p.Gly17Val was by far the most common and occurred in 50 to 60% of cases of AITL and 15 to 20% of PTCL‐NOS. It had previously been recognised that a proportion of cases of PTCL‐NOS have a Tfh phenotype (Rodríguez‐Pinilla et al , ; Manso et al , ) and indeed there is an association between molecular Tfh lymphoma and Tfh marker expression (Watatani et al , ).…”

Section: Genetic Aberrations In Aitl and Ptcl‐nosmentioning

confidence: 99%

The new biology of PTCL‐NOS and AITL: current status and future clinical impact

2020

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Summary Peripheral T‐cell lymphomas (PTCL) comprise a heterogeneous group of aggressive lymphoproliferative disorders almost all of which are associated with poor clinical outcomes. Angioimmunoblastic T‐cell lymphoma (AITL) and some peripheral T‐cell lymphoma, not otherwise specified (PTCL‐NOS) have similarities to normal CD4+ T‐cell subsets in their gene expression profiles. A cell of origin model is, therefore, emerging and is likely to be refined in the future. Follicular helper (Tfh) T cells are now established as the cell of origin of AITL and about 20% of PTCL‐NOS. Sequencing studies have identified recurrent genetic alterations in epigenetic modifiers, T‐cell receptor signalling pathway intermediates or RHOA, most commonly a specific mutation leading to RHOA G17V. While PTCL‐NOS remains a diagnosis of exclusion, advances in genomics have identified subgroups expressing transcription factors TBX 21 (Th1‐like origin) and GATA3 (Th2‐like origin). These findings suggest new biomarkers and new therapeutic avenues including the hypomethylating agent azacytidine, or inhibitors of proximal T‐cell receptor (TCR) signalling and potentially certain monoclonal antibodies. The advances over the past few years, therefore, prompt stratified medicine approaches to test biologically based treatments and determine the clinical utility of the new disease classifications.

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Overlap at the molecular and immunohistochemical levels between angioimmunoblastic T-cell lymphoma and a subgroup of peripheral T-cell lymphomas without specific morphological features

Cited by 29 publications

References 49 publications

Genetic drivers of oncogenic pathways in molecular subgroups of peripheral T-cell lymphoma

Genetic drivers of oncogenic pathways in molecular subgroups of peripheral T-cell lymphoma

Expression of the checkpoint receptors LAG-3, TIM-3 and VISTA in peripheral T cell lymphomas

The new biology of PTCL‐NOS and AITL: current status and future clinical impact

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