Analysis of FOXO1 mutations in diffuse large B-cell lymphoma
Menée sur 22 lignées cellulaires et 279 échantillons prélevés sur des patients atteints d'un lymphome diffus à grandes cellules B, cette étude analyse l'association entre la présence de mutations du gène FOXO1 et la survie des patients traités à l'aide d'un protocole R-CHOP
Diffuse large B-cell lymphoma (DLBCL) accounts for 30% to 40% of newly diagnosed lymphomas and has an overall cure rate of approximately 60%. Previously, we observed FOXO1 mutations in NHL patient samples. To explore the effects of FOXO1 mutations, we assessed FOXO1 status in 279 DLBCL patient samples and 22 DLBCL-derived cell lines. FOXO1 mutations were found in 8.6% (24/279) of DLBCL cases. 92.3% (24/26) of mutations were in the first exon, 46.2% (12/26) were recurrent mutations affecting the N-terminal region and another 38.5% (10/26) affected the Forkhead DNA binding domain. Recurrent mutations in the N-terminal region resulted in diminished T24 phosphorylation, loss of interaction with 14-3-3, and nuclear retention. FOXO1 mutation was associated with decreased overall survival in patients treated with R-CHOP (P = 0.037), independent of cell-of-origin and the Revised International Prognostic Index. This association was particularly evident (P = 0.003) in patients in the low-risk R-IPI categories. The independent relationship of mutations in FOXO1 to survival, transcending the prognostic influence of the R-IPI and COO, indicates that FOXO1 mutation is a novel prognostic factor that plays an important role in DLBCL pathogenesis.
Blood , résumé, 2013