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Abstract: Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of primary cutaneous T-cell lymphoproliferative processes, mainly composed of mycosis fungoides and Sézary syndrome, the aggressive forms of which lack an effective treatment. The molecular pathogenesis of CTCL is largely unknown, although neoplastic cells show increased signaling from T-cell receptors (TCRs). DNAs from 11 patients with CTCL, both normal and tumoral, were target-enriched and sequenced by massive parallel sequencing for a selection of 524 TCR-signaling-related genes. Identified variants were validated by capillary sequencing. Multiple mutations were found that affected several signaling pathways, such as TCRs, nuclear factor ?B, or Janus kinase/signal transducer and activator of transcription, but PLCG1 was found to be mutated in 3 samples, 2 of which featured a redundant mutation (c.1034T>C, S345F) in exon 11 that affects the PLCx protein catalytic domain. This mutation was further analyzed by quantitative polymerase chain reaction genotyping in a new cohort of 42 patients with CTCL, where it was found in 19% of samples. Immunohistochemical analysis for nuclear factor of activated T cells (NFAT) showed that PLCG1-mutated cases exhibited strong NFAT nuclear immunostaining. Functional studies demonstrated that PLCG1 mutants elicited increased downstream signaling toward NFAT activation, and inhibition of this pathway resulted in reduced CTCL cell proliferation and cell viability. Thus, increased proliferative and survival mechanisms in CTCL may partially depend on the acquisition of somatic mutations in PLCG1 and other genes that are essential for normal T-cell differentiation
Fuente: Blood, 2014, 123(13), 2034-2043
Editorial: American Society of Hematology
Año de publicación: 2014
Nº de páginas: 10
Tipo de publicación: Artículo de Revista
DOI: 10.1182/blood-2013-05-504308
ISSN: 0006-4971,1528-0020
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JOSE PEDRO VAQUE DIEZ
GÓMEZ LÓPEZ, GONZALO
MONSÁVEZ, VERÓNICA
IGNACIO VARELA EGOCHEAGA
NEREA MARTINEZ SECO
PÉREZ, CRISTINA
DOMÍNGUEZ, ORLANDO
GRAÑA, OSVALDO
RODRÍGUEZ PERALTO, JOSÉ LUIS
RODRÍGUEZ PINILLA, SOCORRO M
MARIA CARMEN GONZALEZ VELA
RUBIO CAMARILLO, MIRIAM
MARTÍN SÁNCHEZ, ESPERANZA
PISANO, DAVID G
PAPADAVI, EVANGELIA
PAPADAKI, THEODORA
REQUENA, LUIS
GARCÍA MARCO, JOSÉ A
MENDEZ, MIRIAM
PROVENCIO, MARIANO
HOSPITAL, MERCEDES
SUÁREZ MASSA, DOLORES
POSTIGO, CONCEPCIÓN
DAVID SAN SEGUNDO ARRIBAS
MARCOS LOPEZ HOYOS
ORTÍZ ROMERO, PABLO L
MIGUEL ANGEL PIRIS PINILLA
SÁNCHEZ BEATO, MARGARITA
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