Mantle cell lymphoma (MCL), an aggressive subtype of non-Hodgkin lymphoma, is 
characterized by the hallmark translocation t(11;14)(q13;q32) and the resulting 
overexpression of cyclin D1 (CCND1). Our current knowledge of this disease 
encompasses frequent secondary cytogenetic aberrations and the recurrent 
mutation of a handful of genes, such as TP53, ATM, and CCND1. However, these 
findings insufficiently explain the biologic underpinnings of MCL. Here, we 
performed whole transcriptome sequencing on a discovery cohort of 18 primary 
tissue MCL samples and 2 cell lines. We found recurrent mutations in NOTCH1, a 
finding that we confirmed in an extension cohort of 108 clinical samples and 8 
cell lines. In total, 12% of clinical samples and 20% of cell lines harbored 
somatic NOTCH1 coding sequence mutations that clustered in the PEST domain and 
predominantly consisted of truncating mutations or small frame-shifting indels. 
NOTCH1 mutations were associated with poor overall survival (P = .003). 
Furthermore, we showed that inhibition of the NOTCH pathway reduced 
proliferation and induced apoptosis in 2 MCL cell lines. In summary, we have 
identified recurrent NOTCH1 mutations that provide the preclinical rationale for 
therapeutic inhibition of the NOTCH pathway in a subset of patients with MCL.