Angioimmunoblastic T-cell lymphoma and correlated neoplasms with T-cell follicular helper phenotype: from molecular mechanisms to therapeutic advances

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art_LAGE_Angioimmunoblastic_Tcell_lymphoma_and_correlated_neoplasms_with_Tcell_2023.PDF (3.25 MB)
Citações na Scopus
2
Tipo de produção
article
Data de publicação
2023
DOI
Scopus
Web of Science
PubMed
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ISSN da Revista
Título do Volume
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FRONTIERS MEDIA SA
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FRONTIERS IN ONCOLOGY, v.13, article ID 1177590, 18p, 2023
Projetos de Pesquisa
Unidades Organizacionais
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Resumo
Angioimmunoblastic T-cell lymphoma (AITL) is the second most frequent subtype of mature T-cell lymphoma (MTCL) in the Western world. It derives from the monoclonal proliferation of T-follicular helper (TFH) cells and is characterized by an exacerbated inflammatory response and immune dysregulation, with predisposition to autoimmunity phenomena and recurrent infections. Its genesis is based on a multistep integrative model, where age-related and initiator mutations involve epigenetic regulatory genes, such as TET-2 and DNMT3A. Subsequently, driver-mutations, such as RhoA G17V and IDH-2 R172K/S promote the expansion of clonal TFH-cells (""second-hit""), that finally begin to secrete cytokines and chemokines, such as IL-6, IL-21, CXCL-13 and VEGF, modulating a network of complex relationships between TFH-cells and a defective tumor microenvironment (TME), characterized by expansion of follicular dendritic cells (FDC), vessels and EBV-positive immunoblasts. This unique pathogenesis leads to peculiar clinical manifestations, generating the so-called ""immunodysplastic syndrome"", typical of AITL. Its differential diagnosis is broad, involving viral infections, collagenosis and adverse drug reactions, which led many authors to use the term ""many-faced lymphoma"" when referring to AITL. Although great advances in its biological knowledge have been obtained in the last two decades, its treatment is still an unmet medical need, with highly reserved clinical outcomes. Outside the setting of clinical trials, AITL patients are still treated with multidrug therapy based on anthracyclines (CHOP-like), followed by up-front consolidation with autologous stem cell transplantation (ASCT). In this setting, the estimated 5-year overall survival (OS) is around 30-40%. New drugs, such as hypomethylating agents (HMAs) and histone deacetylase inhibitors (HDAi), have been used for relapsed/refractory (R/R) disease with promising results. Such agents have their use based on a biological rationale, have significant potential to improve the outcomes of patients with AITL and may represent a paradigm shift in the therapeutic approach to this lymphoma in the near future.
Palavras-chave
angioimmunoblastic T-cell lymphoma (AITL), T-cell follicular helper phenotype (TFH), epigenetic dysregulation, RhoA G17V mutation, immunodysplastic syndrome, hypomethylating agents (HMAs), histone deacetylase inhibitors (HDAi)
URI
https://observatorio.fm.usp.br/handle/OPI/53787
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