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Molecular Pathogenesis of T Cell Lymphomas
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Molecular Pathogenesis of T Cell Lymphomas

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (30 September 2022) | Viewed by 12096

Special Issue Editor

Prof. Dr. Grzegorz Przybylski

E-Mail Website
Guest Editor
Institute of Human Genetics, Polish Academy of Sciences, 60-479 Poznan, Poland
Interests: leukemia; lymphoma
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

T cell lymphomas (TCL) consists of a heterogenous group of Peripheral T-cell lymphomas (PTCL) and Cutaneous T-cell lymphomas (CTCL), belonging to the most aggressive hematologic neoplasms with poor prognosis. TCL are relatively rare, with the incidence of 0.65/100 000 for PTCL and 0.60/100 000 for CTCL they only consists of 5% of Non-Hodgkin's lymphoma (NHL). The enormous morphologic, immunophenotypic and clinical heterogeneity of TCL reflects the variety of genetic lesions observed in the malignant T cells. In the last ten years, as a result of high throughput whole genome next generation sequencing, the number of genetic aberrations found in TCL increased dramatically. Yet to date the knowledge of genetic alterations has not successfully resulted in better understanding of molecular pathogenesis of distinct TCL entities, and in consequence the prognosis for TCL patients is still unsatisfactorily.

The aim of this Special Issue is to report novel genomic, transcriptomic or proteomic alterations associated with T cell malignancies, as well as functional studies unraveling, or verifying their contribution to the malignant transformation, cancer development or progression. Original articles, short communication and review papers are welcome.

Prof. Dr. Grzegorz Przybylski
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • T cell lymphomas

Published Papers (6 papers)

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12 pages, 2330 KiB  
Article
Differential Response of Mycosis Fungoides Cells to Vorinostat
by Zachary A. Bordeaux, Sriya V. Reddy, Kevin Lee, Weiying Lu, Justin Choi, Meghan Miller, Callie Roberts, Anthony Pollizzi, Shawn G. Kwatra and Madan M. Kwatra
Int. J. Mol. Sci. 2023, 24(9), 8075; https://doi.org/10.3390/ijms24098075 - 29 Apr 2023
Cited by 1 | Viewed by 2030
Abstract
Mycosis fungoides (MF) is the most common form of cutaneous T-cell lymphoma (CTCL) and is characterized by epidermotrophism of malignant CD4+ T-lymphocytes. When MF advances to a recurrent stage, patients require treatment with systemic therapies such as vorinostat, a histone deacetylase inhibitor. While [...] Read more.
Mycosis fungoides (MF) is the most common form of cutaneous T-cell lymphoma (CTCL) and is characterized by epidermotrophism of malignant CD4+ T-lymphocytes. When MF advances to a recurrent stage, patients require treatment with systemic therapies such as vorinostat, a histone deacetylase inhibitor. While vorinostat has been shown to exhibit anti-tumor activity in MF, its exact molecular mechanism has yet to be fully discerned. In the present study, we examined the transcriptomic and proteomic profiles of vorinostat treatment in two MF cell lines, Myla 2059 and HH. We find that vorinostat downregulates CTLA-4, CXCR4, and CCR7 in both cell lines, but its effect on several key pathways differs between the two MF cell lines. For example, vorinostat upregulates CCL5, CCR5, and CXCL10 expression in Myla cells but downregulates CCL5 and CXCL10 expression in HH cells. Furthermore, vorinostat upregulates IFN-γ and IL-23 signaling and downregulates IL-6, IL-7, and IL-15 signaling in Myla cells but does not affect these pathways in HH cells. Although Myla and HH represent established MF cell lines, their distinct tumor origin from separate patients demonstrates that inherent phenotypic variations within the disease persist, underscoring the importance of using a variety of MF cells in the preclinical development of MF therapeutics. Full article
(This article belongs to the Special Issue Molecular Pathogenesis of T Cell Lymphomas)
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11 pages, 2274 KiB  
Article
TMEM244 Is a Long Non-Coding RNA Necessary for CTCL Cell Growth
by Karolina Rassek, Katarzyna Iżykowska, Magdalena Żurawek, Monika Pieniawska, Karina Nowicka, Xing Zhao and Grzegorz K. Przybylski
Int. J. Mol. Sci. 2023, 24(4), 3531; https://doi.org/10.3390/ijms24043531 - 9 Feb 2023
Cited by 1 | Viewed by 1469
Abstract
Transmembrane protein 244 (TMEM244) was annotated to be a member of the TMEM family, which are is a component of cell membranes and is involved in many cellular processes. To date, the expression of the TMEM244 protein has not been experimentally confirmed, and [...] Read more.
Transmembrane protein 244 (TMEM244) was annotated to be a member of the TMEM family, which are is a component of cell membranes and is involved in many cellular processes. To date, the expression of the TMEM244 protein has not been experimentally confirmed, and its function has not been clarified. Recently, the expression of the TMEM244 gene was acknowledged to be a diagnostic marker for Sézary syndrome, a rare cutaneous T-cell lymphoma (CTCL). In this study, we aimed to determine the role of the TMEM244 gene in CTCL cells. Two CTCL cell lines were transfected with shRNAs targeting the TMEM244 transcript. The phenotypic effect of TMEM244 knockdown was validated using green fluorescent protein (GFP) growth competition assays and AnnexinV/7AAD staining. Western blot analysis was performed to identify the TMEM244 protein. Our results indicate that TMEM244 is not a protein-coding gene but a long non-coding RNA (lncRNA) that is necessary for the growth of CTCL cells. Full article
(This article belongs to the Special Issue Molecular Pathogenesis of T Cell Lymphomas)
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15 pages, 2585 KiB  
Article
A Dual Role for FADD in Human Precursor T-Cell Neoplasms
by José Luis Marín-Rubio, Laura Vela-Martín, Jack Gudgeon, Eduardo Pérez-Gómez, Frances R. Sidgwick, Matthias Trost, Debbie L. Cunningham, Javier Santos, José Fernández-Piqueras and María Villa-Morales
Int. J. Mol. Sci. 2022, 23(23), 15157; https://doi.org/10.3390/ijms232315157 - 2 Dec 2022
Viewed by 1642
Abstract
A reduction in FADD levels has been reported in precursor T-cell neoplasms and other tumor types. Such reduction would impact on the ability of tumor cells to undergo apoptosis and has been associated with poor clinical outcomes. However, FADD is also known to [...] Read more.
A reduction in FADD levels has been reported in precursor T-cell neoplasms and other tumor types. Such reduction would impact on the ability of tumor cells to undergo apoptosis and has been associated with poor clinical outcomes. However, FADD is also known to participate in non-apoptotic functions, but these mechanisms are not well-understood. Linking FADD expression to the severity of precursor T-cell neoplasms could indicate its use as a prognostic marker and may open new avenues for targeted therapeutic strategies. Using transcriptomic and clinical data from patients with precursor T-cell neoplasms, complemented by in vitro analysis of cellular functions and by high-throughput interactomics, our results allow us to propose a dual role for FADD in precursor T-cell neoplasms, whereby resisting cell death and chemotherapy would be a canonical consequence of FADD deficiency in these tumors, whereas deregulation of the cellular metabolism would be a relevant non-canonical function in patients expressing FADD. These results reveal that evaluation of FADD expression in precursor T-cell neoplasms may aid in the understanding of the biological processes that are affected in the tumor cells. The altered biological processes can be of different natures depending on the availability of FADD influencing its ability to exert its canonical or non-canonical functions. Accordingly, specific therapeutic interventions would be needed in each case. Full article
(This article belongs to the Special Issue Molecular Pathogenesis of T Cell Lymphomas)
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10 pages, 2775 KiB  
Article
Generation of Inducible BCL11B Knockout in TAL1/LMO1 Transgenic Mouse T Cell Leukemia/Lymphoma Model
by Grzegorz K. Przybylski, Dorota Korsak, Katarzyna Iżykowska, Karina Nowicka, Tomasz Zalewski, Małgorzata Tubacka, Maria Mosor, Danuta Januszkiewicz-Lewandowska, Magdalena Frydrychowicz, Maciej Boruczkowski, Grzegorz Dworacki, Jens van den Brandt, Piotr Grabarczyk, Christian A. Schmidt, Chengwu Zeng and Yangqiu Li
Int. J. Mol. Sci. 2022, 23(9), 4932; https://doi.org/10.3390/ijms23094932 - 29 Apr 2022
Viewed by 2565
Abstract
The B-cell CLL/lymphoma 11B gene (BCL11B) plays a crucial role in T-cell development, but its role in T-cell malignancies is still unclear. To study its role in the development of T-cell neoplasms, we generated an inducible BCL11B knockout in a murine T [...] Read more.
The B-cell CLL/lymphoma 11B gene (BCL11B) plays a crucial role in T-cell development, but its role in T-cell malignancies is still unclear. To study its role in the development of T-cell neoplasms, we generated an inducible BCL11B knockout in a murine T cell leukemia/lymphoma model. Mice, bearing human oncogenes TAL BHLH Transcription Factor 1 (TAL1; SCL) or LIM Domain Only 1 (LMO1), responsible for T-cell acute lymphoblastic leukemia (T-ALL) development, were crossed with BCL11B floxed and with CRE-ER/lox mice. The mice with a single oncogene BCL11Bflox/floxCREtg/tgTAL1tg or BCL11Bflox/floxCREtg/tgLMO1tg were healthy, bred normally, and were used to maintain the mice in culture. When crossed with each other, >90% of the double transgenic mice BCL11Bflox/floxCREtg/tgTAL1tgLMO1tg, within 3 to 6 months after birth, spontaneously developed T-cell leukemia/lymphoma. Upon administration of synthetic estrogen (tamoxifen), which binds to the estrogen receptor and activates the Cre recombinase, the BCL11B gene was knocked out by excision of its fourth exon from the genome. The mouse model of inducible BCL11B knockout we generated can be used to study the role of this gene in cancer development and the potential therapeutic effect of BCL11B inhibition in T-cell leukemia and lymphoma. Full article
(This article belongs to the Special Issue Molecular Pathogenesis of T Cell Lymphomas)
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14 pages, 2166 KiB  
Article
Targeting the DNA Damage Response to Increase Anthracycline-Based Chemotherapy Cytotoxicity in T-Cell Lymphoma
by Martina Magni, Chiara Paolizzi, Chiara Monfrini, Cristina Vella, Paolo Corradini and Cristiana Carniti
Int. J. Mol. Sci. 2022, 23(7), 3834; https://doi.org/10.3390/ijms23073834 - 30 Mar 2022
Viewed by 1981
Abstract
Mature T-cell lymphomas (MTCLs) represent a heterogeneous group of aggressive non-Hodgkin lymphomas comprising different entities. Anthracycline-based regimens are considered the standard of care in the front-line treatment. However, responses to these approaches have been neither adequate nor durable, and new treatment strategies are [...] Read more.
Mature T-cell lymphomas (MTCLs) represent a heterogeneous group of aggressive non-Hodgkin lymphomas comprising different entities. Anthracycline-based regimens are considered the standard of care in the front-line treatment. However, responses to these approaches have been neither adequate nor durable, and new treatment strategies are urgently needed to improve survival. Genomic instability is a common feature of cancer cells and can be caused by aberrations in the DNA damage response (DDR) and DNA repair mechanisms. Consistently, molecules involved in DDR are being targeted to successfully sensitize cancer cells to chemotherapy. Recent studies showed that some hematological malignancies display constitutive DNA damage and intrinsic DDR activation, but these features have not been investigated yet in MTCLs. In this study, we employed a panel of malignant T cell lines, and we report for the first time the characterization of intrinsic DNA damage and basal DDR activation in preclinical models in T-cell lymphoma. Moreover, we report the efficacy of targeting the apical kinase ATM using the inhibitor AZD0156, in combination with standard chemotherapy to promote apoptotic cell death. These findings suggest that DDR is an attractive pathway to be pharmacologically targeted when developing novel therapies and improving MTCL patients’ outcomes. Full article
(This article belongs to the Special Issue Molecular Pathogenesis of T Cell Lymphomas)
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12 pages, 12065 KiB  
Case Report
Molecular Features and Diagnostic Challenges in Alpha/Beta T-Cell Large Granular Lymphocyte Leukemia
by Francesco Gaudio, Pierluigi Masciopinto, Emilio Bellitti, Pellegrino Musto, Elena Arcuti, Olga Battisti, Gerardo Cazzato, Alessandra Solombrino, Filomena Emanuela Laddaga, Giorgina Specchia, Eugenio Maiorano and Giuseppe Ingravallo
Int. J. Mol. Sci. 2022, 23(21), 13392; https://doi.org/10.3390/ijms232113392 - 2 Nov 2022
Cited by 2 | Viewed by 1452
Abstract
Large granular lymphocyte leukemia is a rare chronic lymphoproliferative disease of cytotoxic lymphocytes. The diagnosis, according to the WHO, is based on a persistent (>6 months) increase in the number of LGL cells in the peripheral blood without an identifiable cause. A further [...] Read more.
Large granular lymphocyte leukemia is a rare chronic lymphoproliferative disease of cytotoxic lymphocytes. The diagnosis, according to the WHO, is based on a persistent (>6 months) increase in the number of LGL cells in the peripheral blood without an identifiable cause. A further distinction is made between T-LGL and NK-LGL leukemia. The molecular sign of LGL leukemia is the mutation of STAT3 and other genes associated with the JAK/STAT pathway. The most common clinical features are neutropenia, anemia, and thrombocytopenia, and it is often associated with various autoimmune conditions. It usually has an indolent course. Due to the rarity of the disease, no specific treatment has yet been identified. Immunosuppressive therapy is used and may allow for disease control and long-term survival, but not eradication of the leukemic clone. Here, we discuss the clinical presentation, diagnostic challenges, pathophysiology, and different treatment options available for alpha/beta T-LGL leukemia, which is the most common disease (85%), in order to better understand and manage this often misunderstood disease. Full article
(This article belongs to the Special Issue Molecular Pathogenesis of T Cell Lymphomas)
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