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.