Details

Autor(en) / Beteiligte

• Rossi, Davide
• Trifonov, Vladimir
• Fangazio, Marco
• Bruscaggin, Alessio
• Rasi, Silvia
• Spina, Valeria
• Monti, Sara
• Vaisitti, Tiziana
• Arruga, Francesca
• Famà, Rosella
• Ciardullo, Carmela
• Greco, Mariangela
• Cresta, Stefania
• Piranda, Daniela
• Holmes, Antony
• Fabbri, Giulia
• Messina, Monica
• Rinaldi, Andrea
• Wang, Jiguang
• Agostinelli, Claudio
• Piccaluga, Pier Paolo
• Lucioni, Marco
• Tabbò, Fabrizio
• Serra, Roberto
• Franceschetti, Silvia
• Deambrogi, Clara
• Daniele, Giulia
• Gattei, Valter
• Marasca, Roberto
• Facchetti, Fabio
• Arcaini, Luca
• Inghirami, Giorgio
• Bertoni, Francesco
• Pileri, Stefano A
• Deaglio, Silvia
• Foà, Robin
• Dalla-Favera, Riccardo
• Pasqualucci, Laura
• Rabadan, Raul
• Gaidano, Gianluca

Titel

The coding genome of splenic marginal zone lymphoma: activation of NOTCH2 and other pathways regulating marginal zone development

Ist Teil von

• The Journal of experimental medicine, 2012-08, Vol.209 (9), p.1537-1551

Ort / Verlag

United States: The Rockefeller University Press

Erscheinungsjahr

2012

Quelle

MEDLINE

Beschreibungen/Notizen

• Splenic marginal zone lymphoma (SMZL) is a B cell malignancy of unknown pathogenesis, and thus an orphan of targeted therapies. By integrating whole-exome sequencing and copy-number analysis, we show that the SMZL exome carries at least 30 nonsilent gene alterations. Mutations in NOTCH2, a gene required for marginal-zone (MZ) B cell development, represent the most frequent lesion in SMZL, accounting for ∼20% of cases. All NOTCH2 mutations are predicted to cause impaired degradation of the NOTCH2 protein by eliminating the C-terminal PEST domain, which is required for proteasomal recruitment. Among indolent B cell lymphoproliferative disorders, NOTCH2 mutations are restricted to SMZL, thus representing a potential diagnostic marker for this lymphoma type. In addition to NOTCH2, other modulators or members of the NOTCH pathway are recurrently targeted by genetic lesions in SMZL; these include NOTCH1, SPEN, and DTX1. We also noted mutations in other signaling pathways normally involved in MZ B cell development, suggesting that deregulation of MZ B cell development pathways plays a role in the pathogenesis of ∼60% SMZL. These findings have direct implications for the treatment of SMZL patients, given the availability of drugs that can target NOTCH, NF-κB, and other pathways deregulated in this disease.