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

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

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)1537-1551
Number of pages15
JournalJournal of Experimental Medicine
Volume209
Issue number9
DOIs
Publication statusPublished - Aug 2012

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

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