Buscar

Estamos realizando la búsqueda. Por favor, espere...

 Detalle_Publicacion

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

Abstract: 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-?B pathways. Folliculotropism and large-cell transformation were also examined. RESULTS: NFAT and nuclear factor kappa B (NF-?B) 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-?B 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-?B 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.

 Fuente: Br J Dermatol. 2020 Jan;182(1):147-155

Editorial: Wiley

 Fecha de publicación: 01/01/2020

Nº de páginas: 9

Tipo de publicación: Artículo de Revista

 DOI: 10.1111/bjd.18098

ISSN: 0007-0963,1365-2133

Proyecto español: SAF2013-47416-R

Url de la publicación: https://doi.org/10.1111/bjd.18098

Autores/as

PÉREZ, C.

MONDÉJAR, R.

GARCÍA-DÍAZ, N.

CERECEDA, L.

LEÓN, A.

MONTES, S.

DURÁN VIAN, C.

PÉREZ PAREDES, M.G.

GONZÁLEZ-MORÁN, A.

ALEGRE DE MIGUEL, V.

SANZ ANQUELA, J.M.

FRIAS, J.

LIMERES, M.A.

GONZÁLEZ, L.M.

MARTÍN DÁVILA, F.

BELTRÁN, M.

MOLLEJO, M.

MÉNDEZ, J.R.

GONZÁLEZ, M.A.