Περίληψη:
Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of primary
cutaneous T-cell lymphoproliferative processes, mainly composed of
mycosis fungoides and Sezary 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 kappa 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.
Συγγραφείς:
Vaque, Jose P.
Gomez-Lopez, Gonzalo
Monsalvez, Veronica and
Varela, Ignacio
Martinez, Nerea
Perez, Cristina
Dominguez,
Orlando
Grana, Osvaldo
Rodriguez-Peralto, Jose L. and
Rodriguez-Pinilla, Socorro M.
Gonzalez-Vela, Carmen and
Rubio-Camarillo, Miriam
Martin-Sanchez, Esperanza
Pisano, David
G.
Papadavid, Evangelia
Papadaki, Theodora
Requena, Luis and
Garcia-Marco, Jose A.
Mendez, Miriam
Provencio, Mariano and
Hospital, Mercedes
Suarez-Massa, Dolores
Postigo, Concepcion and
San Segundo, David
Lopez-Hoyos, Marcos
Ortiz-Romero, Pablo L.
and Piris, Miguel A.
Sanchez-Beato, Margarita
