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dc.contributor.authorVaqué, José P.-
dc.contributor.authorVarela, Ignacio-
dc.contributor.authorPiris, Miguel A.-
dc.contributor.authorSánchez-Beato, Margarita-
dc.identifierdoi: 10.1182/blood-2013-05-504308-
dc.identifiere-issn: 1528-0020-
dc.identifierissn: 0006-4971-
dc.identifier.citationBlood 123(13): 2034-2043 (2014)-
dc.description.abstractCutaneous 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.-
dc.description.sponsorshipThis work was supported by grants from the Asociación Española contra el Cancer (AECC), Fondo de Investigaciones Sanitarias (FIS) (RD06/0020/0107, RD012/0036/0060, PI10/00621, PI11/001759, PI12/00357, CP11/00018) Ministerio de Educación y Ciencia (SAF2008-03871). Salary support to MSB is provided by a Miguel Servet contract from FIS. EMS is supported by a grant from the Department of Education, Universities and Research of the Basque Government (BFI08.207). The Instituto para la Formación e Investigación Marqués de Valdecilla (IFIMAV) is partly funded by the Sociedad para el Desarrollo Regional de Cantabria (SODERCAN).-
dc.publisherAmerican Society of Hematology-
dc.titlePLCG1 mutations in cutaneous T-cell lymphomas-
dc.description.versionPeer Reviewed-
dc.contributor.funderAsociación Española Contra el Cáncer-
dc.contributor.funderInstituto de Salud Carlos III-
dc.contributor.funderMinisterio de Educación y Ciencia (España)-
dc.contributor.funderEusko Jaurlaritza-
dc.contributor.funderGobierno de Cantabria-
dc.contributor.funderInstituto de Investigación Marqués de Valdecilla-
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