TY - JOUR
T1 - The coding genome of splenic marginal zone lymphoma
T2 - Activation of NOTCH2 and other pathways regulating marginal zone development
AU - Rossi, Davide
AU - Trifonov, Vladimir
AU - Fangazio, Marco
AU - Bruscaggin, Alessio
AU - Rasi, Silvia
AU - Spina, Valeria
AU - Monti, Sara
AU - Vaisitti, Tiziana
AU - Arruga, Francesca
AU - Famà, Rosella
AU - Ciardullo, Carmela
AU - Greco, Mariangela
AU - Cresta, Stefania
AU - Piranda, Daniela
AU - Holmes, Antony
AU - Fabbri, Giulia
AU - Messina, Monica
AU - Rinaldi, Andrea
AU - Wang, Jiguang
AU - Agostinelli, Claudio
AU - Piccaluga, Pier Paolo
AU - Lucioni, Marco
AU - Tabbò, Fabrizio
AU - Serra, Roberto
AU - Franceschetti, Silvia
AU - Deambrogi, Clara
AU - Daniele, Giulia
AU - Gattei, Valter
AU - Marasca, Roberto
AU - Facchetti, Fabio
AU - Arcaini, Luca
AU - Inghirami, Giorgio
AU - Bertoni, Francesco
AU - Pileri, Stefano A.
AU - Deaglio, Silvia
AU - Foà, Robin
AU - Dalla-Favera, Riccardo
AU - Pasqualucci, Laura
AU - Rabadan, Raul
AU - Gaidano, Gianluca
PY - 2012/8
Y1 - 2012/8
N2 - 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-kB, and other pathways deregulated in this disease.
AB - 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-kB, and other pathways deregulated in this disease.
UR - http://www.scopus.com/inward/record.url?scp=84866429139&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84866429139&partnerID=8YFLogxK
U2 - 10.1084/jem.20120904
DO - 10.1084/jem.20120904
M3 - Article
C2 - 22891273
AN - SCOPUS:84866429139
VL - 209
SP - 1537
EP - 1551
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
SN - 0022-1007
IS - 9
ER -