Peripheral T-cell Lymphoma: From Biological Research to New Therapies

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (15 May 2023) | Viewed by 23523

Special Issue Editors


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Guest Editor
Division of Tumor and Cellular Biochemistry, Department of Medical Sciences, University of Miyazaki, Miyazaki, Japan
Interests: adult T-cell leukemia/lymphoma; HTLV-1; genomic abnormality; signal transduction; immunity; gut microbiota; cellular stress response; epigenetics; autophagy; drug discovery

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Co-Guest Editor
Division of Tumor and Cellular Biochemistry, Department of Medical Sciences, University of Miyazaki, 889-1692 Miyazaki, Japan
Interests: leukemia; stem cells; transcription factor; cancer metabolome; homeostasis; stress responses; retroviral infection

Special Issue Information

Dear Colleagues,

Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of non-Hodgkin lymphomas (NHL) that originates from mature T-cells, including PTCL, not otherwise specified (PTCL-NOS), anaplastic large T-cell lymphoma (ALCL), angioimmunoblastic T-cell lymphoma (AITL), NK/T-cell lymphoma, and adult T-cell leukemia/lymphoma (ATLL). PTCL is generally aggressive and has a poorer prognosis than diffuse large B-cell lymphoma. Genomic analyses of some types of CTCL such as ATLL, ALCL, and PTCL-NOS have been performed so far, and the involvement of important somatic gene alterations including T-cell receptor signaling pathways has been clarified. Furthermore, the relationship between genetic mutations and prognosis and prediction of the effectiveness of anticancer drug treatment have been clarified. However, most PTCL are generally not curable and thus prevention of disease progression and development of new treatments are urgently needed. For this Special Issue, we encourage the submission of original research articles and reviews on any aspect of PTCL, including critical signaling pathways, host immune responses, and novel targeted therapies.


Dr. Shingo Nakahata
Dr. Kazuhiro Morishita
Guest Editors

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Keywords

  • PTCL
  • oncogene
  • tumor suppressor gene
  • cellular signaling pathway
  • host immunity
  • epigenetics
  • drug discovery

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Published Papers (7 papers)

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Editorial

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3 pages, 168 KiB  
Editorial
Peripheral T-Cell Lymphoma: From Biological Research to New Therapies
by Shingo Nakahata and Kazuhiro Morishita
Cancers 2023, 15(16), 4192; https://doi.org/10.3390/cancers15164192 - 21 Aug 2023
Cited by 1 | Viewed by 1266
Abstract
This series of six articles (four reviews and two original articles) is presented by international leaders on peripheral T-cell lymphomas (PTCL) [...] Full article
(This article belongs to the Special Issue Peripheral T-cell Lymphoma: From Biological Research to New Therapies)

Research

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26 pages, 2361 KiB  
Article
Epstein-Barr Virus (EBV) Is Mostly Latent and Clonal in Angioimmunoblastic T Cell Lymphoma (AITL)
by Racha Bahri, François Boyer, Mohamad Adnan Halabi, Alain Chaunavel, Jean Feuillard, Arnaud Jaccard and Sylvie Ranger-Rogez
Cancers 2022, 14(12), 2899; https://doi.org/10.3390/cancers14122899 - 12 Jun 2022
Cited by 10 | Viewed by 3174
Abstract
The Epstein-Barr virus (EBV) is associated with angioimmunoblastic T cell lymphoma (AITL), a peripheral T lymphoma of poor prognosis in at least 90% of cases. The role of EBV in this pathology is unknown. Using next-generation sequencing, we sequenced the entire EBV genome [...] Read more.
The Epstein-Barr virus (EBV) is associated with angioimmunoblastic T cell lymphoma (AITL), a peripheral T lymphoma of poor prognosis in at least 90% of cases. The role of EBV in this pathology is unknown. Using next-generation sequencing, we sequenced the entire EBV genome in biopsies from 18 patients with AITL, 16 patients with another EBV-associated lymphoma, and 2 controls. We chose an EBV target capture method, given the high specificity of this technique, followed by a second capture to increase sensitivity. We identified two main viral strains in AITL, one of them associated with the mutations BNRF1 S542N and BZLF1 A206S and with mutations in the EBNA-3 and LMP-2 genes. This strain was characterized in patients with short post-diagnosis survival. The main mutations found during AITL on the most mutated latency or tegument genes were identified and discussed. We showed that the virus was clonal in all the AITL samples, suggesting that it may be involved in this pathology. Additionally, EBV was latent in all the AITL samples; for one sample only, the virus was found to be latent and probably replicative, depending on the cells. These various elements support the role of EBV in AITL. Full article
(This article belongs to the Special Issue Peripheral T-cell Lymphoma: From Biological Research to New Therapies)
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12 pages, 2484 KiB  
Article
Sting Is Commonly and Differentially Expressed in T- and Nk-Cell but Not B-Cell Non-Hodgkin Lymphomas
by Ioanna Xagoraris, Pedro Farrajota Neves da Silva, Georgia Kokaraki, Konstantina Stathopoulou, Björn Wahlin, Anders Österborg, Nikolas Herold, Siok-Bian Ng, L. Jeffrey Medeiros, Elias Drakos, Birgitta Sander and George Z. Rassidakis
Cancers 2022, 14(5), 1186; https://doi.org/10.3390/cancers14051186 - 24 Feb 2022
Cited by 4 | Viewed by 2924
Abstract
The expression patterns of stimulator of interferon genes (STING) were investigated in a cohort of 158 T- and natural killer (NK)-cell and 265 B-cell non-Hodgkin lymphomas (NHLs), as well as in control reactive lymph nodes and tonsils. STING expression was assessed by immunohistochemical [...] Read more.
The expression patterns of stimulator of interferon genes (STING) were investigated in a cohort of 158 T- and natural killer (NK)-cell and 265 B-cell non-Hodgkin lymphomas (NHLs), as well as in control reactive lymph nodes and tonsils. STING expression was assessed by immunohistochemical methods using diagnostic biopsy specimens obtained prior to treatment. Using an arbitrary 10% cutoff, STING was differentially expressed among T/NK-cell NHLs; positive in 36 out of 38 (95%) cases of ALK+ anaplastic large cell lymphoma (ALCL), 23 out of 37 (62%) ALK-ALCLs, 1 out of 13 (7.7%) angioimmunoblastic T-cell lymphomas, 15 out of 19 (79%) peripheral T-cell lymphomas, not otherwise specified, 20 out of 36 (56%) extranodal NK/T-cell lymphomas of nasal type, 6 out of 7 (86%) T-cell lymphoblastic lymphomas, and 3 out of 4 (75%) mycosis fungoides. STING expression did not correlate with clinicopathological parameters or outcome in these patients with T/NK-cell lymphoma. By contrast, all 265 B-cell NHLs of various types were STING-negative. In addition, STING mRNA levels were very high in 6 out of 7 T-cell NHL cell lines, namely, ALK+ and ALK-ALCL cell lines, and very low or undetectable in 7 B-cell NHL cell lines, suggesting transcriptional downregulation of STING in neoplastic B-cells. At the protein level, using Western blot analysis and immunohistochemistry performed on cell blocks, STING expression was found to be restricted to T-cell NHL cell lines. Taken together, STING expression represents a novel biomarker and therapeutic target in T- and NK-cell lymphomas with direct immunotherapeutic implications since modulators of cGAS–STING activity are already available for clinical use. Full article
(This article belongs to the Special Issue Peripheral T-cell Lymphoma: From Biological Research to New Therapies)
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Review

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19 pages, 16964 KiB  
Review
Mutations Affecting Genes in the Proximal T-Cell Receptor Signaling Pathway in Peripheral T-Cell Lymphoma
by Xiaoqian Liu, Jinyao Ning, Xuxiang Liu and Wing C. (John) Chan
Cancers 2022, 14(15), 3716; https://doi.org/10.3390/cancers14153716 - 29 Jul 2022
Cited by 6 | Viewed by 4328
Abstract
Peripheral T-cell lymphoma (PTCL) comprises a heterogeneous group of mature T-cell malignancies. Recurrent activating mutations and fusions in genes related to the proximal TCR signaling pathway have been identified in preclinical and clinical studies. This review summarizes the genetic alterations affecting proximal TCR [...] Read more.
Peripheral T-cell lymphoma (PTCL) comprises a heterogeneous group of mature T-cell malignancies. Recurrent activating mutations and fusions in genes related to the proximal TCR signaling pathway have been identified in preclinical and clinical studies. This review summarizes the genetic alterations affecting proximal TCR signaling identified from different subgroups of PTCL and the functional impact on TCR signaling and downstream pathways. These genetic abnormalities include mostly missense mutations, occasional indels, and gene fusions involving CD28, CARD11, the GTPase RHOA, the guanine nucleotide exchange factor VAV1, and kinases including FYN, ITK, PLCG1, PKCB, and PI3K subunits. Most of these aberrations are activating mutations that can potentially be targeted by inhibitors, some of which are being tested in clinical trials that are briefly outlined in this review. Finally, we focus on the molecular pathology of recently identified subgroups of PTCL-NOS and highlight the unique genetic profiles associated with PTCL-GATA3. Full article
(This article belongs to the Special Issue Peripheral T-cell Lymphoma: From Biological Research to New Therapies)
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21 pages, 2513 KiB  
Review
The Role of NOTCH1, GATA3, and c-MYC in T Cell Non-Hodgkin Lymphomas
by Mutaz Jamal Al-Khreisat, Faezahtul Arbaeyah Hussain, Ali Mahmoud Abdelfattah, Alhomidi Almotiri, Ola Mohammed Al-Sanabra and Muhammad Farid Johan
Cancers 2022, 14(11), 2799; https://doi.org/10.3390/cancers14112799 - 4 Jun 2022
Cited by 4 | Viewed by 3567
Abstract
Lymphomas are heterogeneous malignant tumours of white blood cells characterised by the aberrant proliferation of mature lymphoid cells or their precursors. Lymphomas are classified into main types depending on the histopathologic evidence of biopsy taken from an enlarged lymph node, progress stages, treatment [...] Read more.
Lymphomas are heterogeneous malignant tumours of white blood cells characterised by the aberrant proliferation of mature lymphoid cells or their precursors. Lymphomas are classified into main types depending on the histopathologic evidence of biopsy taken from an enlarged lymph node, progress stages, treatment strategies, and outcomes: Hodgkin and non-Hodgkin lymphoma (NHL). Moreover, lymphomas can be further divided into subtypes depending on the cell origin, and immunophenotypic and genetic aberrations. Many factors play vital roles in the progression, pathogenicity, incidence, and mortality rate of lymphomas. Among NHLs, peripheral T cell lymphomas (PTCLs) are rare lymphoid malignancies, that have various cellular morphology and genetic mutations. The clinical presentations are usually observed at the advanced stage of the disease. Many recent studies have reported that the expressions of NOTCH1, GATA3, and c-MYC are associated with poorer prognosis in PTCL and are involved in downstream activities. However, questions have been raised about the pathological relationship between these factors in PTCLs. Therefore, in this review, we investigate the role and relationship of the NOTCH1 pathway, transcriptional factor GATA3 and proto-oncogene c-MYC in normal T cell development and malignant PTCL subtypes. Full article
(This article belongs to the Special Issue Peripheral T-cell Lymphoma: From Biological Research to New Therapies)
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20 pages, 10168 KiB  
Review
Novel T Follicular Helper-like T-Cell Lymphoma Therapies: From Preclinical Evaluation to Clinical Reality
by Adrien Krug, Gamze Tari, Aymen Saidane, Philippe Gaulard, Jean-Ehrland Ricci, François Lemonnier and Els Verhoeyen
Cancers 2022, 14(10), 2392; https://doi.org/10.3390/cancers14102392 - 12 May 2022
Cited by 11 | Viewed by 3645
Abstract
The classification of peripheral T-cell lymphomas (PTCL) is constantly changing and contains multiple subtypes. Here, we focus on Tfh-like PTCL, to which angioimmunoblastic T-cell lymphoma (AITL) belongs, according to the last WHO classification. The first-line treatment of these malignancies still relies on chemotherapy [...] Read more.
The classification of peripheral T-cell lymphomas (PTCL) is constantly changing and contains multiple subtypes. Here, we focus on Tfh-like PTCL, to which angioimmunoblastic T-cell lymphoma (AITL) belongs, according to the last WHO classification. The first-line treatment of these malignancies still relies on chemotherapy but gives very unsatisfying results for these patients. Enormous progress in the last decade in terms of understanding the implicated genetic mutations leading to signaling and epigenetic pathway deregulation in Tfh PTCL allowed the research community to propose new therapeutic approaches. These findings point towards new biomarkers and new therapies, including hypomethylating agents, such as azacytidine, and inhibitors of the TCR-hyperactivating molecules in Tfh PTCL. Additionally, metabolic interference, inhibitors of the NF-κB and PI3K-mTOR pathways and possibly novel immunotherapies, such as antibodies and chimeric antigen receptors (CAR) directed against Tfh malignant T-cell surface markers, are discussed in this review among other new treatment options. Full article
(This article belongs to the Special Issue Peripheral T-cell Lymphoma: From Biological Research to New Therapies)
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18 pages, 1710 KiB  
Review
Mother-to-Child Transmission of Human T-Cell Leukemia Virus Type 1: Mechanisms and Nutritional Strategies for Prevention
by Kazuo Itabashi and Tokuo Miyazawa
Cancers 2021, 13(16), 4100; https://doi.org/10.3390/cancers13164100 - 14 Aug 2021
Cited by 17 | Viewed by 3445
Abstract
Approximately 95% of mother-to-child transmission (MTCT) of human T-cell leukemia virus type-1 (HTLV-1) is derived from prolonged breastfeeding, which is a major cause of adult T-cell leukemia (ATL). Exclusive formula feeding (ExFF) is therefore generally used to prevent MTCT. A recent cohort study [...] Read more.
Approximately 95% of mother-to-child transmission (MTCT) of human T-cell leukemia virus type-1 (HTLV-1) is derived from prolonged breastfeeding, which is a major cause of adult T-cell leukemia (ATL). Exclusive formula feeding (ExFF) is therefore generally used to prevent MTCT. A recent cohort study revealed that 55% of pregnant carriers chose short-term breastfeeding for ≤3 months in Japan. Our meta-analysis showed that there was no significant increase in the risk of MTCT when breastfeeding was carried out for ≤3 months compared with ExFF (pooled relative risk (RR), 0.72; 95% confidence interval (CI), 0.30–1.77), but there was an almost threefold increase in risk when breastfeeding was carried out for up to 6 months (pooled RR, 2.91; 95% CI, 1.69–5.03). Thus, short-term breastfeeding for ≤3 months may be useful in preventing MTCT. Breastmilk is the best nutritional source for infants, and any approach to minimizing MTCT by avoiding or limiting breastfeeding must be balanced against the impact on the child’s health and mother–child bonding. To minimize the need for nutritional interventions, it is necessary to identify factors that predispose children born to carrier mothers to MTCT and thereby predict MTCT development with a high degree of accuracy. Full article
(This article belongs to the Special Issue Peripheral T-cell Lymphoma: From Biological Research to New Therapies)
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