Cutaneous Lymphoma Molecular Pathogenesis, Diagnosis and Management

Editors


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Collection Editor
1. Division of Dermatology, McGill University Health Centre, Montreal, QC, Canada
2. President-Elect, Skin Research Group of Canada, Montreal, QC, Canada
Interests: cutaneous lymphoma; melanoma; basal cell carcinoma; carcinoma; squamous cell carcinoma
Special Issues, Collections and Topics in MDPI journals

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Collection Editor
Division of Dermatology, Department of Medicine, University of Alberta, Edmonton, AB, Canada
Interests: cutaneous lymphoma; psoriasis; genomics
Special Issues, Collections and Topics in MDPI journals

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Collection Editor
1. Professor and Head of Inflammation & Cancer; Department of Immunology and Microbiology, Copenhagen, Denmark
2. Professor, LEO Foundation Skin Immunology Research Center; University of Copenhagen, Copenhagen, Denmark
Interests: cutaneous T-cell lymphoma

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Collection Editor
University of Texas MD Anderson Cancer Center, Houston, TX, USA
Interests: cutaneous T-cell lymphoma; mycosis fungoides; Sézary Syndrome

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Collection Editor
Director of The Cutaneous Lymphoma Program and Extracorporeal Photopheresis Unit, Department of Dermatology, University of Pittsburgh, Pittsburgh, PA, USA
Interests: cutaneous lymphoma

Topical Collection Information

Dear Colleagues,

Primary cutaneous lymphomas are classified based on the type of malignant cells driving the disease process: primary cutaneous B-cell lymphomas (PCBCLs) or primary cutaneous T-cell lymphomas (CTCL). CTCLs are a heterogeneous group of lymphoid malignancies derived from skin-homing T-cells. CTCLs account for 75% of all cutaneous lymphomas. While, Mycosis fungoides (MF), primary cutaneous Anaplastic Large Cell Lymphoma (and other CD30+ lymphoproliferative malignancies), and Sézary Syndrome represent the commonly recognized forms of the disease, other variants as defined by the WHO-EORTC classification are becoming increasingly prevalent (e.g., primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder and others). CTCL can be difficult to diagnose as it often mimics other dermatoses such as chronic eczema, psoriasis, drug eruptions, or skin infections. Skin biopsy and the detection of T-cell receptor (TCR) clonality are often not diagnostic for this malignancy. As a result, it takes on average ~6 years to establish the diagnosis of CTCL. Currently, there are no validated molecular markers to help identify this cancer and shorten the time to diagnosis. Furthermore, while >70% of patients present with stage I disease, only 20%–30% of them progress to higher stages. Currently, it is difficult to predict which patients will progress and which ones will experience an indolent disease course. Despite the available new treatments, the survival of patients with advanced CTCL remains poor (2–4 years).

PCBCL is a group of extranodal B-cell non-Hodgkin lymphomas that involve the skin. They account for approximately 25% of all cutaneous lymphomas and are classified as primary cutaneous marginal zone lymphoma (PCMZL), primary cutaneous follicle-center cell lymphoma (PCFCL), and diffuse large B-cell lymphoma, leg type (PCDLBCL, LT). Recently, Epstein–Barr virus positive (EBV+) mucocutaneous ulcer (EB-MCU) was added as a new provisional distinct entity. PCBCLs conventionally present as violaceous plaques, or nodules. Diagnosis requires skin biopsy and histological examination with appropriate immunohistochemical staining.

While certain external triggers/promoters (e.g., Borrelia burgdorferi for PCMZL, S. Aureus for CTCL or Human T-Cell Lymphotropic virus (HTLV-1) for Adult T-Cell Leukemia/Lymphoma) have been identified or suspected, the pathogenesis of both PCBCL and CTCL remains elusive. The field lacks reliable diagnostic markers for CTCL, or prognostic markers for both CTCL and PCBCL as well as novel therapeutic targets.

This Topical Collection is dedicated to research that can enhance our understanding of the molecular pathogenesis and evolution of cutaneous lymphomas, the genetics/genomic components of the disease, the diagnostic/prognostic markers, the role of the microbiome, as well as novel avenues for treating these challenging diseases.

Dr. Ivan V. Litvinov
Dr. Robert Gniadecki
Dr. Niels Ødum
Dr. Madeleine Duvic
Dr. Oleg Akilov
Collection Editors

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Keywords

  • cutaneous lymphoma
  • cutaneous T-cell lymphoma (CTCL)
  • primary cutaneous B-cell lymphoma (PCBCL)
  • pagetoid reticulosis
  • folliculotropic mycosis fungoides
  • granulomatous slack skin
  • hypopigmented mycosis fungoides
  • poikilodermatous mycosis fungoides
  • erythodermic mycosis fungoides
  • primary cutaneous marginal zone lymphomas
  • primary cutaneous follicle center cell lymphomas
  • primary cutaneous large B-cell lymphomas
  • intravascular large B-cell lymphomas
  • Sezary syndrome
  • subcutaneous panniculitis-like T-cell lymphoma
  • lymphomatoid papulosis
  • CD30-positive anaplastic large-cell lymphoma
  • primary CD30-positive lymphoproliferative disorders
  • extranodal NK/T-cell lymphoma; nasal type
  • adult T-cell leukemia/lymphoma
  • human T-cell lymphotropic virus (HTLV)
  • thymocyte selection-associated HMG bOX (TOX)

Published Papers (16 papers)

2024

Jump to: 2023, 2022, 2021, 2020

16 pages, 1041 KiB  
Review
Vitamin D in Cutaneous T-Cell Lymphoma
by August-Witte Feentved Ødum and Carsten Geisler
Cells 2024, 13(6), 503; https://doi.org/10.3390/cells13060503 - 13 Mar 2024
Cited by 1 | Viewed by 1339
Abstract
Cutaneous T-cell lymphoma (CTCL) is characterized by the proliferation of malignant T cells in inflamed skin lesions. Mycosis fungoides (MF)—the most common variant of CTCL—often presents with skin lesions around the abdomen and buttocks (“bathing suit” distribution), i.e., in skin areas devoid of [...] Read more.
Cutaneous T-cell lymphoma (CTCL) is characterized by the proliferation of malignant T cells in inflamed skin lesions. Mycosis fungoides (MF)—the most common variant of CTCL—often presents with skin lesions around the abdomen and buttocks (“bathing suit” distribution), i.e., in skin areas devoid of sun-induced vitamin D. For decades, sunlight and vitamin D have been connected to CTCL. Thus, vitamin D induces apoptosis and inhibits the expression of cytokines in malignant T cells. Furthermore, CTCL patients often display vitamin D deficiency, whereas phototherapy induces vitamin D and has beneficial effects in CTCL, suggesting that light and vitamin D have beneficial/protective effects in CTCL. Inversely, vitamin D promotes T helper 2 (Th2) cell specific cytokine production, regulatory T cells, tolerogenic dendritic cells, as well as the expression of immune checkpoint molecules, all of which may have disease-promoting effects by stimulating malignant T-cell proliferation and inhibiting anticancer immunity. Studies on vitamin D treatment in CTCL patients showed conflicting results. Some studies found positive effects, others negative effects, while the largest study showed no apparent clinical effect. Taken together, vitamin D may have both pro- and anticancer effects in CTCL. The balance between the opposing effects of vitamin D in CTCL is likely influenced by treatment and may change during the disease course. Therefore, it remains to be discovered whether and how the effect of vitamin D can be tilted toward an anticancer response in CTCL. Full article
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2023

Jump to: 2024, 2022, 2021, 2020

14 pages, 643 KiB  
Review
What Does the Future Hold for Biomarkers of Response to Extracorporeal Photopheresis for Mycosis Fungoides and Sézary Syndrome?
by Oleg E. Akilov
Cells 2023, 12(18), 2321; https://doi.org/10.3390/cells12182321 - 20 Sep 2023
Cited by 1 | Viewed by 966
Abstract
Extracorporeal photopheresis (ECP) is an FDA-approved immunotherapy for cutaneous T-cell lymphoma, which can provide a complete response in some patients. However, it is still being determined who will respond well, and predictive biomarkers are urgently needed to target patients for timely treatment and [...] Read more.
Extracorporeal photopheresis (ECP) is an FDA-approved immunotherapy for cutaneous T-cell lymphoma, which can provide a complete response in some patients. However, it is still being determined who will respond well, and predictive biomarkers are urgently needed to target patients for timely treatment and to monitor their response over time. The aim of this review is to analyze the current state of the diagnostic, prognostic, and disease state-monitoring biomarkers of ECP, and outline the future direction of the ECP biomarker discovery. Specifically, we focus on biomarkers of response to ECP in mycosis fungoides and Sézary syndrome. The review summarizes the current knowledge of ECP biomarkers, including their limitations and potential applications, and identifies key challenges in ECP biomarker discovery. In addition, we discuss emerging technologies that could revolutionize ECP biomarker discovery and accelerate the translation of biomarker research into clinical practice. This review will interest researchers and clinicians seeking to optimize ECP therapy for cutaneous T-cell lymphoma. Full article
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2022

Jump to: 2024, 2023, 2021, 2020

18 pages, 1431 KiB  
Review
Targeting the CD47-SIRPα Axis: Present Therapies and the Future for Cutaneous T-cell Lymphoma
by Amy Xiao and Oleg E. Akilov
Cells 2022, 11(22), 3591; https://doi.org/10.3390/cells11223591 - 13 Nov 2022
Cited by 5 | Viewed by 4125
Abstract
The loss of CD47 on aging cells serves as a signal to macrophages to eliminate the target. Therefore, CD47 is a “do-not-eat-me” sign preventing macrophagal phagocytosis via interaction with its ligand SIRPα. Malignant lymphocytes of mycosis fungoides and Sézary syndrome express CD47 highly, [...] Read more.
The loss of CD47 on aging cells serves as a signal to macrophages to eliminate the target. Therefore, CD47 is a “do-not-eat-me” sign preventing macrophagal phagocytosis via interaction with its ligand SIRPα. Malignant lymphocytes of mycosis fungoides and Sézary syndrome express CD47 highly, thus, being ideal candidates for targeted anti-CD47 therapies. The classes of current anti-CD47-SIRPα therapeutic molecules present in a large variety and include monoclonal antibodies against CD47 and SIRPα, bioengineered SIRPα proteins, miRNAs, and bispecific antibodies. We provided a detailed analysis of all available investigational drugs in a contest of cutaneous T-cell lymphoma. A combination of blockade of the CD47-SIRPα axis and secondary targets in the tumor microenvironment (TME) may improve the clinical efficacy of current immunotherapeutic approaches. We evaluated the possible combination and outlined the most promising one. Full article
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21 pages, 6278 KiB  
Article
The Role of the Immune Phenotype in Tumor Progression and Prognosis of Patients with Mycosis Fungoides: A Quantitative Immunohistology Whole Slide Approach
by Natallia Aulasevich, Maximilian Haist, Sebastian Försch, Beate Weidenthaler-Barth and Volker Mailänder
Cells 2022, 11(22), 3570; https://doi.org/10.3390/cells11223570 - 11 Nov 2022
Cited by 3 | Viewed by 1460
Abstract
Background and objectives: Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphomas, characterized by mature, skin-tropic CD4+ T-helper cells. In order to study the immune tumor microenvironment in MF patients, we performed immunohistochemical stains on MF biopsies, digitized whole-slide tissue [...] Read more.
Background and objectives: Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphomas, characterized by mature, skin-tropic CD4+ T-helper cells. In order to study the immune tumor microenvironment in MF patients, we performed immunohistochemical stains on MF biopsies, digitized whole-slide tissue sections, and performed quantitative analysis of the different immune cell subsets to correlate tissue parameters with the clinical data of patients, such as progression-free survival or overall survival. Patients and methods: Overall, 35 patients who were treated between 2009 and 2019 and for whom one or more paraffin tissue blocks were available have been included in the present study (58 tissue specimens in total). Conventional immunohistochemistry stains for CD3, CD4, CD8, CD20 and CD30 were used for the analysis of the immune phenotype, and quantitative analysis was performed using QuPath as a quantitative digital pathology tool for bioimage analysis of whole slides. Results: Analysis of tissue parameters for prognostic significance revealed that patients with a stronger infiltration by CD8+ lymphocytes within the tumor cell compartment had a higher risk of disease progression (p = 0.031) and showed a shorter progress-free survival (p = 0.038). Furthermore, a significant association of the percentage of CD30+ cells (median: 7.8%) with the risk of disease progression (p = 0.023) and progression-free survival (p = 0.023) was found. In relation to the clinical features of our patient cohort, a higher risk of disease progression (p = 0.015) and a shorter progression-free survival (p = 0.032) for older patients (>61 years) were observed. Conclusions: Our results demonstrated the prognostic relevance of large-cell transformation in mycosis fungoides and its strong association with the presence of CD30+ lymphocytes. Unlike previous reports, our study suggests an adverse prognostic role for CD8+ T cells in patients with mycosis fungoides. Moreover, our data indicate that the immune phenotype within the tumor microenvironment shows strong temporal heterogeneity and is altered in the course of tumor progression. Full article
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17 pages, 38664 KiB  
Article
Mass Cytometric Analysis of Early-Stage Mycosis Fungoides
by Nannan Guo, Li Jia, Coby Out-Luiting, Noel F. C. C. de Miranda, Rein Willemze, Frits Koning, Maarten Vermeer and Koen Quint
Cells 2022, 11(7), 1062; https://doi.org/10.3390/cells11071062 - 22 Mar 2022
Cited by 2 | Viewed by 3173
Abstract
Mycosis fungoides (MF) is the most common subtype of cutaneous T-cell lymphoma. Early-stage disease is characterized by superficial infiltrates of small- to medium-sized atypical epidermotropic T lymphocytes that are clonal related. Nevertheless, the percentage of atypical T cells is low with many admixed [...] Read more.
Mycosis fungoides (MF) is the most common subtype of cutaneous T-cell lymphoma. Early-stage disease is characterized by superficial infiltrates of small- to medium-sized atypical epidermotropic T lymphocytes that are clonal related. Nevertheless, the percentage of atypical T cells is low with many admixed reactive immune cells. Despite earlier studies, the composition and spatial characteristics of the cutaneous lymphocytic infiltrate has been incompletely characterized. Here, we applied mass cytometry to profile the immune system in skin biopsies of patients with early-stage MF and in normal skin from healthy individuals. Single-cell suspensions were prepared and labeled with a 43-antibody panel, and data were acquired on a Helios mass cytometer. Unbiased hierarchical clustering of the data identified the major immune lineages and heterogeneity therein. This revealed patient-unique cell clusters in both the CD4+ and myeloid cell compartments but also phenotypically distinct cell clusters that were shared by most patients. To characterize the immune compartment in the tissue context, we developed a 36-antibody panel and performed imaging mass cytometry on MF skin tissue. This visualized the structure of MF skin and the distribution of CD4+ T cells, regulatory T cells, CD8+ T cells, malignant T cells, and various myeloid cell subsets. We observed clusters of CD4+ T cells and multiple types of dendritic cells (DCs) identified through differential expression of CD11c, CD1a, and CD1c in the dermis. These results indicated substantial heterogeneity in the composition of the local immune infiltrate but suggest a prominent role for clustered CD4–DC interactions in disease pathogenesis. Probably, the local inhibition of such interactions may constitute an efficient treatment modality. Full article
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21 pages, 347 KiB  
Review
Understanding Cell Lines, Patient-Derived Xenograft and Genetically Engineered Mouse Models Used to Study Cutaneous T-Cell Lymphoma
by Raman Preet Kaur Gill, Jennifer Gantchev, Amelia Martínez Villarreal, Brandon Ramchatesingh, Elena Netchiporouk, Oleg E. Akilov, Niels Ødum, Robert Gniadecki, Sergei B. Koralov and Ivan V. Litvinov
Cells 2022, 11(4), 593; https://doi.org/10.3390/cells11040593 - 9 Feb 2022
Cited by 7 | Viewed by 3555
Abstract
Cutaneous T cell lymphoma (CTCL) is a spectrum of lymphoproliferative disorders caused by the infiltration of malignant T cells into the skin. The most common variants of CTCL include mycosis fungoides (MF), Sézary syndrome (SS) and CD30+ Lymphoproliferative disorders (CD30+ LPDs). [...] Read more.
Cutaneous T cell lymphoma (CTCL) is a spectrum of lymphoproliferative disorders caused by the infiltration of malignant T cells into the skin. The most common variants of CTCL include mycosis fungoides (MF), Sézary syndrome (SS) and CD30+ Lymphoproliferative disorders (CD30+ LPDs). CD30+ LPDs include primary cutaneous anaplastic large cell lymphoma (pcALCL), lymphomatoid papulosis (LyP) and borderline CD30+ LPD. The frequency of MF, SS and CD30+ LPDs is ~40–50%, <5% and ~10–25%, respectively. Despite recent advances, CTCL remains challenging to diagnose. The mechanism of CTCL carcinogenesis still remains to be fully elucidated. Hence, experiments in patient-derived cell lines and xenografts/genetically engineered mouse models (GEMMs) are critical to advance our understanding of disease pathogenesis. To enable this, understanding the intricacies and limitations of each individual model system is highly important. Presently, 11 immortalized patient-derived cell lines and different xenograft/GEMMs are being used to study the pathogenesis of CTCL and evaluate the therapeutic efficacy of various treatment modalities prior to clinical trials. Gene expression studies, and the karyotyping analyses of cell lines demonstrated that the molecular profile of SeAx, Sez4, SZ4, H9 and Hut78 is consistent with SS origin; MyLa and HH resemble the molecular profile of advanced MF, while Mac2A and PB2B represent CD30+ LPDs. Molecular analysis of the other two frequently used Human T-Cell Lymphotropic Virus-1 (HTLV-1)+ cell lines, MJ and Hut102, were found to have characteristics of Adult T-cell Leukemia/Lymphoma (ATLL). Studies in mouse models demonstrated that xenograft tumors could be grown using MyLa, HH, H9, Hut78, PB2B and SZ4 cells in NSG (NOD Scid gamma mouse) mice, while several additional experimental GEMMs were established to study the pathogenesis, effect of drugs and inflammatory cytokines in CTCL. The current review summarizes cell lines and xenograft/GEMMs used to study and understand the etiology and heterogeneity of CTCL. Full article
8 pages, 2804 KiB  
Article
Sézary Syndrome: Different Erythroderma Morphological Features with Proposal for a Clinical Score System
by Gabriele Roccuzzo, Silvia Giordano, Gianluca Avallone, Marco Rubatto, Silvia Canonico, Ada Funaro, Erika Ortolan, Rebecca Senetta, Paolo Fava, Maria Teresa Fierro, Simone Ribero and Pietro Quaglino
Cells 2022, 11(3), 333; https://doi.org/10.3390/cells11030333 - 20 Jan 2022
Cited by 2 | Viewed by 4366
Abstract
Sézary syndrome is a rare subtype of cutaneous T-cell lymphoma characterized by erythroderma, peripheral lymphadenopathies, and circulating atypical cerebriform T-cells. To date, no definite staging system has been developed for these patients. In this retrospective analysis of the archive of the Dermatological Clinic [...] Read more.
Sézary syndrome is a rare subtype of cutaneous T-cell lymphoma characterized by erythroderma, peripheral lymphadenopathies, and circulating atypical cerebriform T-cells. To date, no definite staging system has been developed for these patients. In this retrospective analysis of the archive of the Dermatological Clinic of the University of Turin, Italy, erythrodermic SS patients were classified according to clinical records and photographs into three main presentations: erythematous, infiltrated, or melanodermic. The pattern of erythroderma was found to be associated with disease outcome, as better survivals were recorded in patients with erythematous and infiltrative erythroderma. Patients in the melanodermic group, though less represented in our investigation, seemed to show a worse trend in survival. According to this preliminary evidence, a new prognostic classification, with a revised score specific for Sézary syndrome patients, can be proposed to usefully integrate the current staging system. The correlation displayed in our research will be hopefully confirmed by prospective studies with larger cohorts, with the aim of identifying significant prognostic features in this subset of cutaneous T-cell lymphoma patients. Full article
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18 pages, 2195 KiB  
Review
Transcriptional Heterogeneity and the Microbiome of Cutaneous T-Cell Lymphoma
by Philipp Licht and Volker Mailänder
Cells 2022, 11(3), 328; https://doi.org/10.3390/cells11030328 - 19 Jan 2022
Cited by 9 | Viewed by 4186
Abstract
Cutaneous T-Cell Lymphomas (CTCL) presents with substantial clinical variability and transcriptional heterogeneity. In the recent years, several studies paved the way to elucidate aetiology and pathogenesis of CTCL using sequencing methods. Several T-cell subtypes were suggested as the source of disease thereby explaining [...] Read more.
Cutaneous T-Cell Lymphomas (CTCL) presents with substantial clinical variability and transcriptional heterogeneity. In the recent years, several studies paved the way to elucidate aetiology and pathogenesis of CTCL using sequencing methods. Several T-cell subtypes were suggested as the source of disease thereby explaining clinical and transcriptional heterogeneity of CTCL entities. Several differentially expressed pathways could explain disease progression. However, exogenous triggers in the skin microenvironment also seem to affect CTCL status. Especially Staphylococcus aureus was shown to contribute to disease progression. Only little is known about the complex microbiome patterns involved in CTCL and how microbial shifts might impact this malignancy. Nevertheless, first hints indicate that the microbiome might at least in part explain transcriptional heterogeneity and that microbial approaches could serve in diagnosis and prognosis. Shaping the microbiome could be a treatment option to maintain stable disease. Here, we review current knowledge of transcriptional heterogeneity of and microbial influences on CTCL. We discuss potential benefits of microbial applications and microbial directed therapies to aid patients with CTCL burden. Full article
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2021

Jump to: 2024, 2023, 2022, 2020

4 pages, 203 KiB  
Communication
Strategies to Optimize Adherence in Patients with Mycosis Fungoides
by Warren H. Chan, Daniel J. Lewis, Madeleine Duvic and Steven R. Feldman
Cells 2022, 11(1), 113; https://doi.org/10.3390/cells11010113 - 30 Dec 2021
Cited by 1 | Viewed by 1577
Abstract
Patient adherence to medications for common skin conditions has been extensively studied over the past two decades, and suboptimal adherence is a primary contributor to treatment failure. The impact of sub-par adherence in cutaneous T-cell lymphoma (CTCL) patients has been largely unexplored, and [...] Read more.
Patient adherence to medications for common skin conditions has been extensively studied over the past two decades, and suboptimal adherence is a primary contributor to treatment failure. The impact of sub-par adherence in cutaneous T-cell lymphoma (CTCL) patients has been largely unexplored, and promoting adherence in this patient population may represent a promising area of consideration for improving treatment outcomes. We apply patient adherence strategies that have been studied in dermatology to CTCL and provide concrete examples of how these strategies can be used to improve adherence in the CTCL setting. Through the implementation of small changes in how we present and counsel about therapeutic options to our patients, we can maximize patient adherence, which has the potential to optimize therapy regimens and reduce treatment failure. Full article
13 pages, 1571 KiB  
Article
Gene Expression Profiling of Mycosis Fungoides in Early and Tumor Stage—A Proof-of-Concept Study Using Laser Capture/Single Cell Microdissection and NanoString Analysis
by Justine Lai, Jing Li, Robert Gniadecki and Raymond Lai
Cells 2021, 10(11), 3190; https://doi.org/10.3390/cells10113190 - 16 Nov 2021
Cited by 1 | Viewed by 2129
Abstract
A subset of patients with mycosis fungoides (MF) progress to the tumor stage, which correlates with a worse clinical outcome. The molecular events driving this progression are not well-understood. To identify the key molecular drivers, we performed gene expression profiling (GEP) using NanoString. [...] Read more.
A subset of patients with mycosis fungoides (MF) progress to the tumor stage, which correlates with a worse clinical outcome. The molecular events driving this progression are not well-understood. To identify the key molecular drivers, we performed gene expression profiling (GEP) using NanoString. Ten formalin-fixed/paraffin-embedded skin biopsies from six patients (six non-tumor and four tumor MF) were included; non-tumor and tumor samples were available in three patients. Laser capture/single cell microdissection of epidermotropic MF cells was used for non-tumor cases. We found that the RNA extracted from 700–800 single cells was consistently sufficient for GEP, provided that multiplexed target enrichment amplification was used. An un-supervised/hierarchical analysis revealed clustering of non-tumor and tumor cases. Many of the most upregulated or downregulated genes are implicated in the PI3K, RAS, cell cycle/apoptosis and MAPK pathways. Two of the targets, HMGA1 and PTPN11 (encodes SHP2), were validated using immunohistochemistry. HMGA1 was positive in six out of six non-tumor MF samples and negative in five out of five tumor MF samples. An opposite pattern was seen with SHP2. Our study has provided a proof-of-concept that single-cell microdissection/GEP can be applied to archival tissues. Some of our identified gene targets might be key drivers of the disease progression of MF. Full article
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17 pages, 1462 KiB  
Review
Chemokines and Innate Lymphoid Cells in Skin Inflammation
by Zhengwang Sun, Ravi Vattepu and Songfa Zhang
Cells 2021, 10(11), 3074; https://doi.org/10.3390/cells10113074 - 8 Nov 2021
Cited by 12 | Viewed by 3593
Abstract
As the outermost barrier, skin plays an important role in protecting our bodies against outside invasion. Under stable conditions or during inflammation, leukocytes migration is essential for restoring homeostasis in the skin. Immune cells trafficking is orchestrated by chemokines; leukocytes express receptors that [...] Read more.
As the outermost barrier, skin plays an important role in protecting our bodies against outside invasion. Under stable conditions or during inflammation, leukocytes migration is essential for restoring homeostasis in the skin. Immune cells trafficking is orchestrated by chemokines; leukocytes express receptors that bind to chemokines and trigger migration. The homeostasis of the immune ecosystem is an extremely complicated dynamic process that requires the cooperation of innate and adaptive immune cells. Emerging studies have been shedding a light on the unique characteristics of skin-resident innate lymphoid cells (ILCs). In this review, we discuss how chemokines orchestrate skin ILCs trafficking and contribute to tissue homeostasis and how abnormal chemokine–chemokine receptor interactions contribute to and augment skin inflammation, as seen in conditions such as contact hypersensitivity, atopic dermatitis, and psoriasis. Full article
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23 pages, 3146 KiB  
Review
The Microenvironment’s Role in Mycosis Fungoides and Sézary Syndrome: From Progression to Therapeutic Implications
by Alessandro Pileri, Alba Guglielmo, Vieri Grandi, Silvia Alberti Violetti, Daniele Fanoni, Paolo Fava, Claudio Agostinelli, Emilio Berti, Pietro Quaglino and Nicola Pimpinelli
Cells 2021, 10(10), 2780; https://doi.org/10.3390/cells10102780 - 17 Oct 2021
Cited by 18 | Viewed by 6582
Abstract
Background: Mycosis fungoides (MF) and Sezary Syndrome (SS) are the most common cutaneous T-cell lymphomas. It has been hypothesized that the interaction between the immune system, cutaneous cells, and neoplastic elements may play a role in MF/SS pathogenesis and progression. Methods: This paper [...] Read more.
Background: Mycosis fungoides (MF) and Sezary Syndrome (SS) are the most common cutaneous T-cell lymphomas. It has been hypothesized that the interaction between the immune system, cutaneous cells, and neoplastic elements may play a role in MF/SS pathogenesis and progression. Methods: This paper aims to revise in a narrative way our current knowledge of the microenvironment’s role in MF/SS. Results and Conclusions: Literature data support a possible implication of microenvironment cells in MF/SS pathogenesis and progression, opening up new therapeutic avenues. Full article
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9 pages, 1585 KiB  
Article
Evaluation of the International Society for Cutaneous Lymphoma Algorithm for the Diagnosis of Early Mycosis Fungoides
by Hyang-Joo Ryu, Sun-Il Kim, Hyung-Ook Jang, Se-Hoon Kim, Sang-Ho Oh, Sujin Park and Sang-Kyum Kim
Cells 2021, 10(10), 2758; https://doi.org/10.3390/cells10102758 - 15 Oct 2021
Cited by 7 | Viewed by 2734
Abstract
The International Society for Cutaneous Lymphoma (ISCL) proposes a diagnostic algorithm for early mycosis fungoides (MF) that includes clinical, histological, immunophenotypical, and molecular criteria. Here, we analyzed the immunologic markers and features of T-cell clonality in 38 early MF cases and 22 non-MF [...] Read more.
The International Society for Cutaneous Lymphoma (ISCL) proposes a diagnostic algorithm for early mycosis fungoides (MF) that includes clinical, histological, immunophenotypical, and molecular criteria. Here, we analyzed the immunologic markers and features of T-cell clonality in 38 early MF cases and 22 non-MF cases to validate the ISCL algorithm. We found that CD5 and CD7 expression differed significantly between early MF and non-MF cases, with epidermal discordance of CD7 expression more frequently identified in early MF. Notably, increasing the cut-off value for CD7 expression from 10% to 22.5% improved its sensitivity. Furthermore, TCR-γ and β chain rearrangements were more frequently detected in early MF than in non-MF cases. Based on these findings, we propose CD5 and CD7 deficiency as mandatory immunopathologic criteria and PCR-based testing for TCR-γ and β chains as required molecular/biologic criteria to improve the efficiency of early MF diagnosis using the ISCL algorithm. Full article
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17 pages, 1437 KiB  
Systematic Review
Patterns of Gene Expression in Cutaneous T-Cell Lymphoma: Systematic Review of Transcriptomic Studies in Mycosis Fungoides
by Melika Motamedi, Maggie Z. X. Xiao, Aishwarya Iyer and Robert Gniadecki
Cells 2021, 10(6), 1409; https://doi.org/10.3390/cells10061409 - 6 Jun 2021
Cited by 5 | Viewed by 3150
Abstract
Mycosis fungoides (MF) is the most prevalent type of skin lymphoma. In its early stages, it has a favorable prognosis. However, in its late stages, it is associated with an increased risk of mortality. This systematic review aimed to identify the transcriptomic changes [...] Read more.
Mycosis fungoides (MF) is the most prevalent type of skin lymphoma. In its early stages, it has a favorable prognosis. However, in its late stages, it is associated with an increased risk of mortality. This systematic review aimed to identify the transcriptomic changes involved in MF pathogenesis and progression. A literature search was conducted using the database PubMed, followed by the extraction of 2245 genes which were further filtered to 150 recurrent genes that appeared in two or more publications. Categorization of these genes identified activated pathways involved in pathways such as cell cycle and proliferation, chromosomal instability, and DNA repair. We identified 15 genes implicated in MF progression, which were involved in cell proliferation, immune checkpoints, resistance to apoptosis, and immune response. In highlighting the discrepancies in the way MF transcriptomic data is obtained, further research can focus on not only unifying their approach but also focus on the 150 pertinent genes identified in this review. Full article
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14 pages, 1777 KiB  
Article
Targeting Cutaneous T-Cell Lymphoma Cells by Ingenol Mebutate (PEP005) Correlates with PKCδ Activation, ROS Induction as Well as Downregulation of XIAP and c-FLIP
by Uly Sumarni, Ulrich Reidel and Jürgen Eberle
Cells 2021, 10(5), 987; https://doi.org/10.3390/cells10050987 - 23 Apr 2021
Cited by 4 | Viewed by 2504
Abstract
New therapeutic strategies are needed for cutaneous T-cell lymphoma (CTCL), and the plant extract ingenol mebutate (PEP005) may be considered. PEP005 has been approved for actinic keratosis, and proapoptotic activities were described in different cancer cells. Here, we aimed to investigate its efficacy [...] Read more.
New therapeutic strategies are needed for cutaneous T-cell lymphoma (CTCL), and the plant extract ingenol mebutate (PEP005) may be considered. PEP005 has been approved for actinic keratosis, and proapoptotic activities were described in different cancer cells. Here, we aimed to investigate its efficacy in four CTCL cell lines and its mode of action. While HuT-78 and HH responded with induced apoptosis as well as with loss of cell viability and cell proliferation, MyLa and SeAx remained resistant. Interestingly, both sensitive and resistant cells showed caspase-8 activation and enhanced levels of reactive oxygen species (ROS), while final caspase-3 activation was restricted to sensitive cells. Apoptosis induction was prevented by the caspase inhibitor QVD-Oph as well as by the antioxidant vitamin E. Caspase activation by PEP005 may be explained to some extent by the downregulation of the caspase antagonistic proteins c-FLIP and XIAP in sensitive cells, whereas both proteins were strongly expressed in resistant cells. Finally, PEP005 resulted in the activation of proapoptotic PKCδ, and the PKC inhibitor bisindolylmaleimide I reduced apoptosis, caspase-3 processing and ROS production, as well as restored cell viability. In conclusion, PKCδ appeared as a central player in apoptosis regulation in CTCL cells, also suggesting its therapeutic targeting. Full article
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2020

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12 pages, 1500 KiB  
Article
Epigenetic Silencing of Tumor Suppressor miR-124 Directly Supports STAT3 Activation in Cutaneous T-Cell Lymphoma
by Lidia García-Colmenero, Jéssica González, Juan Sandoval, Yolanda Guillén, Angel Diaz-Lagares, Evelyn Andrades, Arnau Iglesias, Lara Nonell, Ramon Maria Pujol, Anna Bigas, Lluís Espinosa and Fernando Gallardo
Cells 2020, 9(12), 2692; https://doi.org/10.3390/cells9122692 - 15 Dec 2020
Cited by 7 | Viewed by 2317
Abstract
Increasing evidence supports a potential role for STAT3 as a tumor driver in cutaneous T-cell lymphomas (CTCL). The mechanisms leading to STAT3 activation are not fully understood; however, we recently found that miR-124, a known STAT3 regulator, is robustly silenced in MF tumor-stage [...] Read more.
Increasing evidence supports a potential role for STAT3 as a tumor driver in cutaneous T-cell lymphomas (CTCL). The mechanisms leading to STAT3 activation are not fully understood; however, we recently found that miR-124, a known STAT3 regulator, is robustly silenced in MF tumor-stage and CTCL cells. Objective: We studied here whether deregulation of miR-124 contributes to STAT3 pathway activation in CTCL. Methods: We measured the effect of ectopic mir-124 expression in active phosphorylated STAT3 (p-STAT3) levels and evaluated the transcriptional impact of miR-124-dependent STAT3 pathway regulation by expression microarray analysis. Results: We found that ectopic expression of miR-124 results in massive downregulation of activated STAT3 in different CTCL lines, which resulted in a significant alteration of genetic signatures related with gene transcription and proliferation such as MYC and E2F. Conclusions: Our study highlights the importance of the miR-124/STAT3 axis in CTCL and demonstrates that the STAT3 pathway is regulated through epigenetic mechanisms in these cells. Since deregulated STAT3 signaling has a major impact on CTCL initiation and progression, a better understanding of the molecular basis of the miR-124/STAT3 axis may provide useful information for future personalized therapies. Full article
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