Advanced-stage mycosis fungoides: role of the signal transducer and activator of transcription 3, nuclear factor-κB and nuclear factor of activated T cells pathways.

Autor: Pérez C; Translational Hematopathology, Instituto de Investigación Marqués de Valdecilla, IDIVAL, Santander, Spain.; Centro de Investigación Biomédica en Red Cáncer, Madrid, Spain., Mondéjar R; Translational Hematopathology, Instituto de Investigación Marqués de Valdecilla, IDIVAL, Santander, Spain.; Centro de Investigación Biomédica en Red Cáncer, Madrid, Spain.; Service of Pathology, Fundación Jiménez Díaz University Hospital, Madrid, Spain., García-Díaz N; Departamento de Biología Molecular, Universidad de Cantabria, Infección, Inmunidad y Patología Digestive, Instituto de Investigación Marqués de Valdecilla, IDIVAL, Santander, Spain., Cereceda L; Centro de Investigación Biomédica en Red Cáncer, Madrid, Spain.; Service of Pathology, Fundación Jiménez Díaz University Hospital, Madrid, Spain., León A; Pathology Service, Marqués de Valdecilla University Hospital, Santander, Spain., Montes S; Centro de Investigación Biomédica en Red Cáncer, Madrid, Spain.; Pathology Service, Marqués de Valdecilla University Hospital, Santander, Spain., Durán Vian C; Dermatology Service, Marqués de Valdecilla University Hospital, Santander, Spain., Pérez Paredes MG; Dermatology Service, Marqués de Valdecilla University Hospital, Santander, Spain., González-Morán A; Dermatology Service, Complejo Hospitalario de Ávila, Ávila, Spain., Alegre de Miguel V; Dermatology Service, Hospital General Universitario de Valencia, Valencia, Spain., Sanz Anquela JM; Cancer Registry and Pathology Department, Hospital Universitario Príncipe de Asturias and Department of Medicine and Medical Specialties, Faculty of Medicine, University of Alcalá, Alcalá de Henares, Madrid, Spain., Frias J; Dermatology Service, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain., Limeres MA; Pathology Department, Hospital Universitario de Gran Canaria Doctor Negrín, Gran Canaria, Canarias, Spain., González LM; Pathology Service, Hospital General Universitario de Ciudad Real, Ciudad Real, Spain., Martín Dávila F; Pathology Service, Hospital General Universitario de Ciudad Real, Ciudad Real, Spain., Beltrán M; Pathology Service, Hospital Universitario Puerta del Mar, Cádiz, Spain., Mollejo M; Pathology Service, Complejo Hospitalario de Toledo, Toledo, Spain., Méndez JR; Pathology Service, Centro Médico de Asturias, Asturias, Spain., González MA; Pathology Service, Hospital San Pedro de Alcántara, Cáceres, Spain., González García J; Pathology Service, Hospital General Universitario de Ciudad Real, Ciudad Real, Spain., López R; Pathology Service, Hospital General Universitario de Ciudad Real, Ciudad Real, Spain., Gómez A; Pathology Service, Hospital de la Marina Baixa, Alicante, Spain., Izquierdo F; Pathology Service, Complejo Asistencial Universitario de León, León, Spain., Ramos R; Pathology Service, University Hospital Son Espases, Palma de Mallorca, Spain., Camacho C; Pathology Service, C.H.U. Insular - Materno Infantil, Gran Canarias, Spain., Rodriguez-Pinilla SM; Centro de Investigación Biomédica en Red Cáncer, Madrid, Spain.; Service of Pathology, Fundación Jiménez Díaz University Hospital, Madrid, Spain., Martínez N; Translational Hematopathology, Instituto de Investigación Marqués de Valdecilla, IDIVAL, Santander, Spain.; Centro de Investigación Biomédica en Red Cáncer, Madrid, Spain., Vaqué JP; Departamento de Biología Molecular, Universidad de Cantabria, Infección, Inmunidad y Patología Digestive, Instituto de Investigación Marqués de Valdecilla, IDIVAL, Santander, Spain., Ortiz-Romero PL; Centro de Investigación Biomédica en Red Cáncer, Madrid, Spain.; Dermatology Service, Hospital 12 de Octubre, Institute i+12 Medical School, University Complutense, Centro de Investigación Biomédica en Red Cáncer, Madrid, Spain., Piris MA; Centro de Investigación Biomédica en Red Cáncer, Madrid, Spain.; Service of Pathology, Fundación Jiménez Díaz University Hospital, Madrid, Spain.
Jazyk: angličtina
Zdroj: The British journal of dermatology [Br J Dermatol] 2020 Jan; Vol. 182 (1), pp. 147-155. Date of Electronic Publication: 2019 Jul 25.
DOI: 10.1111/bjd.18098
Abstrakt: Background: The malignant mechanisms that control the development of cutaneous T-cell lymphoma (CTCL) are beginning to be identified. Recent evidence suggests that disturbances in specific intracellular signalling pathways, such as RAS-mitogen-activated protein kinase, T-cell receptor (TCR)-phospholipase C gamma 1 (PLCG1)-nuclear factor of activated T cells (NFAT) and Janus kinase (JAK)-signal transducer and activator of transcription (STAT), may play an essential role in the pathogenesis of CTCL.
Objectives: To investigate the mechanisms controlling disease development and progression in mycosis fungoides (MF), the most common form of CTCL.
Methods: We collected 100 samples that were submitted for diagnosis of, or a second opinion regarding, MF between 2001 and 2018, 80% of which were in the early clinical stages of the disease. Formalin-fixed paraffin-embedded tissues were used for histological review and to measure the expression by immunohistochemistry of surrogate markers of activation of the TCR-PLCG1-NFAT, JAK-STAT and NF-κB pathways. Folliculotropism and large-cell transformation were also examined.
Results: NFAT and nuclear factor kappa B (NF-κB) markers showed a comparable activation status in early and advanced stages, while STAT3 activation was more frequent in advanced stages and was associated with large-cell transformation. Consistently with this observation, STAT3 activation occurred in parallel with MF progression in two initially MF-negative cases. A significant association of NFAT with NF-κB markers was also found, reflecting a common mechanism of activation in the two pathways. Genomic studies identified nine mutations in seven genes known to play a potential role in tumorigenesis in T-cell leukaemia/lymphoma, including PLCG1, JAK3 and STAT3, which underlies the activation of these key cell-survival pathways. A higher mutational allele frequency was detected in advanced stages.
Conclusions: Our results show that STAT3 is activated in advanced cases and is associated with large-cell transformation, while the activation of NFAT and NF-κB is maintained throughout the disease. These findings could have important diagnostic and therapeutic implications. What's already known about this topic? Mycosis fungoides is characterized by a clonal expansion of T cells in the skin. The mechanisms controlling disease development and progression are not fully understood. What does this study add? An association of the nuclear factor of activated T cells and nuclear factor kappa B pathways was found, which could reflect a common mechanism of activation. These pathways were activated in early and advanced stages at the same level. Signal transducer and activator of transcription 3 activation was associated with large-cell transformation and was more frequent in advanced stages. A genomic analysis of cutaneous T-cell lymphoma-associated genes was performed. Nine mutations were detected. What is the translational message? These results could have important implications for the treatment of MF in the near future.
(© 2019 British Association of Dermatologists.)
Databáze: MEDLINE
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