The coding genome of splenic marginal zone lymphoma: activation of NOTCH2 and other pathways regulating marginal zone development.
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.
Division of Hematology and 9 Laboratory of Medical Informatics, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, 28100 Novara, Italy.
Davide
D
Rossi
Vladimir
V
Trifonov
Marco
M
Fangazio
Alessio
A
Bruscaggin
Silvia
S
Rasi
Valeria
V
Spina
Sara
S
Monti
Tiziana
T
Vaisitti
Francesca
F
Arruga
Rosella
R
Famà
Carmela
C
Ciardullo
Mariangela
M
Greco
Stefania
S
Cresta
Daniela
D
Piranda
Antony
A
Holmes
Giulia
G
Fabbri
Monica
M
Messina
Andrea
A
Rinaldi
Jiguang
J
Wang
Claudio
C
Agostinelli
Pier Paolo
PP
Piccaluga
Marco
M
Lucioni
Fabrizio
F
Tabbò
Roberto
R
Serra
Silvia
S
Franceschetti
Clara
C
Deambrogi
Giulia
G
Daniele
Valter
V
Gattei
Roberto
R
Marasca
Fabio
F
Facchetti
Luca
L
Arcaini
Giorgio
G
Inghirami
Francesco
F
Bertoni
Stefano A
SA
Pileri
Silvia
S
Deaglio
Robin
R
Foà
Riccardo
R
Dalla-Favera
Laura
L
Pasqualucci
Raul
R
Rabadan
Gianluca
G
Gaidano
D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D042002:Chromatin Assembly and Disassembly; D004268:DNA-Binding Proteins; D059472:Exome; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D016328:NF-kappa B / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D016601:RNA-Binding Proteins; D051881:Receptor, Notch1 / Q000235:genetics; D051883:Receptor, Notch2 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013160:Splenic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D016328:NF-kappa B; C497761:NOTCH1 protein, human; C497764:NOTCH2 protein, human; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; D051881:Receptor, Notch1; D051883:Receptor, Notch2; C476510:SPEN protein, human