Cancers

Research

Jump to: Review

8 pages, 1737 KiB

Open AccessCommunication

T-Cell Receptor Rearrangements in Early Stages of Mycosis Fungoides May Be Associated with Pronounced Copy Number Variations: A Prognostic Factor?

by Carsten Hain, Cassandra Cieslak, Jörn Kalinowski and Rudolf Stadler

Cancers 2025, 17(3), 556; https://doi.org/10.3390/cancers17030556 - 6 Feb 2025

Viewed by 701

Abstract

Mycosis fungoides (MF), the most common form of cutaneous T-cell lymphoma, poses significant diagnostic challenges due to its overlap with benign inflammatory skin diseases and the absence of specific symptoms. Accurate early diagnosis and stratification of patients by progression risk are essential for [...] Read more.

Mycosis fungoides (MF), the most common form of cutaneous T-cell lymphoma, poses significant diagnostic challenges due to its overlap with benign inflammatory skin diseases and the absence of specific symptoms. Accurate early diagnosis and stratification of patients by progression risk are essential for effective treatment. This study proposes a proof-of-concept for integrating T-cell receptor (TCR) clonality analysis with somatic mutation profiling to enhance diagnostic confidence and prognostic accuracy in early-stage MF. This study’s methodology comprised the analysis of nine patients with early MF (stages IA/IB) using whole-exome sequencing and TCR repertoire profiling. The analysis revealed the presence of clonal TCR rearrangements in seven patients, while somatic mutations were identified in two. A notable finding was a recurrent chromosome 7 trisomy in these two cases. The patients were stratified into three molecular profiles: (1) somatic mutations with clonal TCR rearrangement (n = 2), (2) clonal TCR rearrangement without somatic mutations (n = 4), and (3) neither somatic mutations nor clonal TCR rearrangement (n = 3). These findings emphasise the heterogeneity of MF and underscore the limitations of relying solely on TCR clonality or mutation burden for diagnosis. This study underscores the potential of somatic mutations as diagnostic markers to distinguish MF from benign conditions and as prognostic indicators for disease progression. A combined genetic approach may refine treatment decisions, particularly for patients with higher tumor cell fractions and pronounced genetic alterations. Despite the limited size of the cohort, the results advocate for larger, multi-center studies to validate these findings and integrate genetic analyses into routine MF management. Full article

(This article belongs to the Special Issue Oncogenesis of Lymphoma)

► Show Figures

Figure 1

24 pages, 18716 KiB

Open AccessArticle

Multi-Omic Data Integration Suggests Putative Microbial Drivers of Aetiopathogenesis in Mycosis Fungoides

by Philipp Licht and Volker Mailänder

Cancers 2024, 16(23), 3947; https://doi.org/10.3390/cancers16233947 - 25 Nov 2024

Cited by 1 | Viewed by 1491

Abstract

Background: Mycosis fungoides (MF) represents the most prevalent entity of cutaneous T cell lymphoma (CTCL). The MF aetiopathogenesis is incompletely understood, due to significant transcriptomic heterogeneity and conflicting views on whether oncologic transformation originates in early thymocytes or mature effector memory T cells. [...] Read more.

Background: Mycosis fungoides (MF) represents the most prevalent entity of cutaneous T cell lymphoma (CTCL). The MF aetiopathogenesis is incompletely understood, due to significant transcriptomic heterogeneity and conflicting views on whether oncologic transformation originates in early thymocytes or mature effector memory T cells. Recently, using clinical specimens, our group showed that the skin microbiome aggravates disease course, mainly driven by an outgrowing, pathogenic S. aureus strain carrying the virulence factor spa, which was shown by others to activate the T cell signalling pathway NF-κB. Methods: To explore the role of the skin microbiome in MF aetiopathogenesis, we here performed RNA sequencing, multi-omic data integration of the skin microbiome and skin transcriptome using Multi-Omic Factor Analysis (MOFA), virome profiling, and T cell receptor (TCR) sequencing in 10 MF patients from our previous study group. Results: We observed that inter-patient transcriptional heterogeneity may be largely attributed to differential activation of T cell signalling pathways. Notably, the MOFA model resolved the heterogenous activation pattern of T cell signalling after denoising the transcriptome from microbial influence. The MOFA model suggested that the outgrowing S. aureus strain evoked signalling by non-canonical NF-κB and IL-1B, which in turn may have fuelled the aggravated disease course. Further, the MOFA model indicated aberrant pathways of early thymopoiesis alongside enrichment of antiviral innate immunity. In line with this, viral prevalence, particularly of Epstein–Barr virus (EBV), trended higher in both lesional skin and the blood compared to nonlesional skin. Additionally, TCRs in both MF skin lesions and the blood were significantly more likely to recognize EBV peptides involved in latent infection. Conclusions: First, our findings suggest that S. aureus with its virulence factor spa fuels MF progression through non-canonical NF-κB and IL-1B signalling. Second, our data provide insights into the potential role of viruses in MF aetiology. Last, we propose a model of microbiome-driven MF aetiopathogenesis: Thymocytes undergo initial oncologic transformation, potentially caused by viruses. After maturation and skin infiltration, an outgrowing, pathogenic S. aureus strain evokes activation and maturation into effector memory T cells, resulting in aggressive disease. Further studies are warranted to verify and extend our data, which are based on computational analyses. Full article

(This article belongs to the Special Issue Oncogenesis of Lymphoma)

► Show Figures

Figure 1

Review

Jump to: Research

23 pages, 1576 KiB

Open AccessReview

Immune Deficiency/Dysregulation-Associated EBV-Positive Classic Hodgkin Lymphoma

by Mohamed Nazem Alibrahim, Annunziata Gloghini and Antonino Carbone

Cancers 2025, 17(9), 1433; https://doi.org/10.3390/cancers17091433 - 25 Apr 2025

Viewed by 1268

Abstract

Classic Hodgkin lymphoma (cHL) in patients with immune deficiency/dysregulation represents a critical unmet need in hematology, demanding the appropriate revision of classification and therapeutic paradigms. Epstein–Barr virus (EBV) is a pivotal driver of lymphomagenesis in this high-risk subset, where viral oncoproteins (e.g., LMP1/2A) [...] Read more.

Classic Hodgkin lymphoma (cHL) in patients with immune deficiency/dysregulation represents a critical unmet need in hematology, demanding the appropriate revision of classification and therapeutic paradigms. Epstein–Barr virus (EBV) is a pivotal driver of lymphomagenesis in this high-risk subset, where viral oncoproteins (e.g., LMP1/2A) exploit immune vulnerabilities to activate NF-κB, rewire tumor microenvironments (TME), and evade immune surveillance. EBV-positive cHL, prevalent in immunosuppressed populations, exhibits distinct molecular hallmarks, including reduced somatic mutations, unique HLA associations, and profound PD-L1-mediated immune suppression, that diverge from EBV-negative cases reliant on genetic aberrations. Despite advances in combined antiretroviral therapy, HIV co-infection exacerbates pathogenesis, M2 macrophage dominance, and T-cell exhaustion, while links to other viruses remain ambiguous. Current therapies fail to adequately target these viral and immune complexities, leaving patients with poorer outcomes. This review synthesizes insights into EBV’s etiological role, immune contexture disparities, and the genetic–environmental interplay shaping cHL heterogeneity. The WHO classification highlights the need to reclassify EBV-associated cHL as a distinct subset, integrating viral status and immune biomarkers into diagnostic frameworks. Urgent priorities include global epidemiological studies to clarify causal mechanisms, development of virus-targeted therapies (e.g., EBV-specific T-cell strategies, PD-1/CTLA-4 blockade), and personalized regimens for immune-dysregulated cohorts. Full article

(This article belongs to the Special Issue Oncogenesis of Lymphoma)

► Show Figures

Figure 1

25 pages, 1453 KiB

Open AccessReview

Molecular Mechanisms in the Transformation from Indolent to Aggressive B Cell Malignancies

by Nawar Maher, Samir Mouhssine, Bassam Francis Matti, Alaa Fadhil Alwan and Gianluca Gaidano

Cancers 2025, 17(5), 907; https://doi.org/10.3390/cancers17050907 - 6 Mar 2025

Viewed by 877

Abstract

Histological transformation (HT) into aggressive lymphoma is a turning point in a significant fraction of patients affected by indolent lymphoproliferative neoplasms, namely, chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), marginal zone lymphomas (MZLs), and lymphoplasmacytic lymphoma (LPL) [...] Full article

(This article belongs to the Special Issue Oncogenesis of Lymphoma)

► Show Figures

Figure 1

30 pages, 2446 KiB

Open AccessReview

The Functional Interaction Between Epstein–Barr Virus and MYC in the Pathogenesis of Burkitt Lymphoma

by Sandra Solares, Javier León and Lucía García-Gutiérrez

Cancers 2024, 16(24), 4212; https://doi.org/10.3390/cancers16244212 - 18 Dec 2024

Viewed by 2462

Abstract

The Epstein–Barr virus (EBV) is associated with a wide range of diseases, malignant and non-malignant. EBV was, in fact, the first virus described with cell transformation capacity, discovered by Epstein in 1964 in lymphoma samples from African children. Since then, EBV has been [...] Read more.

The Epstein–Barr virus (EBV) is associated with a wide range of diseases, malignant and non-malignant. EBV was, in fact, the first virus described with cell transformation capacity, discovered by Epstein in 1964 in lymphoma samples from African children. Since then, EBV has been associated with several human tumors including nasopharyngeal carcinoma, gastric carcinoma, T-cell lymphoma, Hodgkin lymphoma, diffuse large B cell lymphoma, and Burkitt lymphoma among others. The molecular hallmark of Burkitt lymphoma (BL) is a chromosomal translocation that involves the MYC gene and immunoglobulin loci, resulting in the deregulated expression of MYC, an oncogenic transcription factor that appears deregulated in about half of human tumors. The role of MYC in lymphoma is well established, as MYC overexpression drives B cell proliferation through multiple mechanisms, foremost, the stimulation of the cell cycle. Indeed, MYC is found overexpressed or deregulated in several non-Hodgkin lymphomas. Most endemic and many sporadic BLs are associated with EBV infection. While some mechanisms by which EBV can contribute to BL have been reported, the mechanism that links MYC translocation and EBV infection in BL is still under debate. Here, we review the main EBV-associated diseases, with a special focus on BL, and we discuss the interaction of EBV and MYC translocation during B cell malignant transformation in BL. Full article

(This article belongs to the Special Issue Oncogenesis of Lymphoma)

► Show Figures

Figure 1

16 pages, 603 KiB

Open AccessReview

Pathobiological Features and Therapeutic Opportunities Linked to TNF Family Member Expression in Classic Hodgkin Lymphoma

by Mohamed N. Alibrahim, Annunziata Gloghini and Antonino Carbone

Cancers 2024, 16(23), 4070; https://doi.org/10.3390/cancers16234070 - 5 Dec 2024

Cited by 2 | Viewed by 2032

Abstract

The tumor necrosis factor (TNF) family, which includes 19 ligands and 29 receptors, influences cellular proliferation, differentiation, and apoptosis. The TNF family plays a crucial role in the pathogenesis of Hodgkin lymphoma (HL), particularly through its influence on the tumor microenvironment (TME). Hodgkin [...] Read more.

The tumor necrosis factor (TNF) family, which includes 19 ligands and 29 receptors, influences cellular proliferation, differentiation, and apoptosis. The TNF family plays a crucial role in the pathogenesis of Hodgkin lymphoma (HL), particularly through its influence on the tumor microenvironment (TME). Hodgkin Reed–Sternberg (HRS) cells, the hallmark of classic HL (cHL), exhibit overexpression of TNF receptor family members such as CD30 and CD40. Given the critical roles of CD30 and CD40 in the survival and proliferation of HRS cells within the TME, targeting these TNF receptors represents a promising therapeutic strategy; therapies that target CD30 have already shown efficacy in clinical settings. The programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) axis plays a crucial role in immune evasion by HRS cells, which express PD-L1 that interacts with PD-1 on T cells, leading to T cell exhaustion and a diminished immune response against the tumor. By blocking this interaction, checkpoint inhibitors such as nivolumab and pembrolizumab have demonstrated high response rates in patients with cHL, particularly in those who have not responded to conventional therapies. The integration of immune checkpoint inhibitors (ICIs) with standard chemotherapy regimens has improved outcomes for patients with advanced-stage cHL. By understanding how TNF signaling interacts with immune checkpoints, researchers can design more effective treatment regimens that simultaneously target multiple pathways. Combining TNF inhibitors with checkpoint blockade therapies may enhance the overall anti-tumor response by addressing both direct tumor signaling and the immune evasion mechanisms employed by tumor cells. Full article

(This article belongs to the Special Issue Oncogenesis of Lymphoma)

► Show Figures

Figure 1

14 pages, 610 KiB

Open AccessReview

Increased c-MYC Expression Associated with Active IGH Locus Rearrangement: An Emerging Role for c-MYC in Chronic Lymphocytic Leukemia

by Kenza Guiyedi, Milène Parquet, Said Aoufouchi, Jasmine Chauzeix, David Rizzo, Israa Al Jamal, Jean Feuillard, Nathalie Gachard and Sophie Peron

Cancers 2024, 16(22), 3749; https://doi.org/10.3390/cancers16223749 - 6 Nov 2024

Viewed by 1487

Abstract

This review examines the pivotal role of c-MYC in Chronic Lymphocytic Leukemia (CLL), focusing on how its overexpression leads to increased genetic instability, thereby accelerating disease progression. MYC, a major oncogene, encodes a transcription factor that regulates essential cellular processes, including cell [...] Read more.

This review examines the pivotal role of c-MYC in Chronic Lymphocytic Leukemia (CLL), focusing on how its overexpression leads to increased genetic instability, thereby accelerating disease progression. MYC, a major oncogene, encodes a transcription factor that regulates essential cellular processes, including cell cycle control, proliferation, and apoptosis. In CLL cases enriched with unmutated immunoglobulin heavy chain variable (IGHV) genes, MYC is significantly overexpressed and associated with active rearrangements in the IGH immunoglobulin heavy chain locus. This overexpression results in substantial DNA damage, including double-strand breaks, chromosomal translocations, and an increase in abnormal repair events. Consequently, c-MYC plays a dual role in CLL: it promotes aggressive cell proliferation while concurrently driving genomic instability through its involvement in genetic recombination. This dynamic contributes not only to CLL progression but also to the overall aggressiveness of the disease. Additionally, the review suggests that c-MYC’s influence on genetic rearrangements makes it an attractive target for therapeutic strategies aimed at mitigating CLL malignancy. These findings underscore c-MYC’s critical importance in advancing CLL progression, highlighting the need for further research to explore its potential as a target in future treatment approaches. Full article

(This article belongs to the Special Issue Oncogenesis of Lymphoma)

► Show Figures

Figure 1

19 pages, 2151 KiB

Open AccessReview

Molecular Mechanisms of Kaposi Sarcoma-Associated Herpesvirus (HHV8)-Related Lymphomagenesis

by Caroline J. Yu and Blossom Damania

Cancers 2024, 16(21), 3693; https://doi.org/10.3390/cancers16213693 - 31 Oct 2024

Viewed by 2307

Abstract

Approximately 15–20% of cancers are caused by viruses. Kaposi sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8 (HHV8), is an oncogenic virus that is the etiologic agent of not only Kaposi sarcoma but also the lymphoproliferative disorders, primary effusion lymphoma (PEL) and [...] Read more.

Approximately 15–20% of cancers are caused by viruses. Kaposi sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8 (HHV8), is an oncogenic virus that is the etiologic agent of not only Kaposi sarcoma but also the lymphoproliferative disorders, primary effusion lymphoma (PEL) and multicentric Castleman disease (MCD). KSHV can infect a broad tropism of cells, including B lymphocytes, wherein KSHV encodes specific viral proteins that can transform the cell. KSHV infection precedes the progression of PEL and MCD. KSHV establishes lifelong infection and has two phases of its lifecycle: latent and lytic. During the latent phase, viral genomes are maintained episomally with limited gene expression. Upon sporadic reactivation, the virus enters its replicative lytic phase to produce infectious virions. KSHV relies on its viral products to modulate host factors to evade immune detection or to co-opt their function for KSHV persistence. These manipulations dysregulate normal cell pathways to ensure cell survival and inhibit antiviral immune responses, which in turn, contribute to KSHV-associated malignancies. Here, we highlight the known molecular mechanisms of KSHV that promote lymphomagenesis and how these findings identify potential therapeutic targets for KSHV-associated lymphomas. Full article

(This article belongs to the Special Issue Oncogenesis of Lymphoma)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Oncogenesis of Lymphoma

Share This Special Issue

Special Issue Editors

Special Issue Information

Keywords

Benefits of Publishing in a Special Issue

Published Papers (8 papers)

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI