PLCG1 mutations in cutaneous T-cell lymphomas.
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 κB, 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.
Instituto Formación Investigación Hospital Universitario Marqués de Valdecilla, Santander, Spain;
José P
JP
Vaqué
Gonzalo
G
Gómez-López
Verónica
V
Monsálvez
Ignacio
I
Varela
Nerea
N
Martínez
Cristina
C
Pérez
Orlando
O
Domínguez
Osvaldo
O
Graña
José L
JL
Rodríguez-Peralto
Socorro M
SM
Rodríguez-Pinilla
Carmen
C
González-Vela
Miriam
M
Rubio-Camarillo
Esperanza
E
Martín-Sánchez
David G
DG
Pisano
Evangelia
E
Papadavid
Theodora
T
Papadaki
Luis
L
Requena
José A
JA
García-Marco
Miriam
M
Méndez
Mariano
M
Provencio
Mercedes
M
Hospital
Dolores
D
Suárez-Massa
Concepción
C
Postigo
David
D
San Segundo
Marcos
M
López-Hoyos
Pablo L
PL
Ortiz-Romero
Miguel A
MA
Piris
Margarita
M
Sánchez-Beato
D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D016399:Lymphoma, T-Cell / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D009154:Mutation; D041681:NIH 3T3 Cells; D051966:Phospholipase C gamma / Q000235:genetics*; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology
C522157:PLCG1 protein, human; D051966:Phospholipase C gamma