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.
ANALYSIS OF THE CODING GENOME OF SPLENIC MARGINAL ZONE LYMPHOMA REVEALS MUTATIONAL ACTIVATION OF NOTCH2 AND OTHER PATHWAYS REGULATING MARGINAL ZONE DIFFERENTIATION / D Rossi; V Trifonov; M Fangazio; A Bruscaggin; S Rasi; V Spina; S Monti; T Vaisitti; F Arruga; R Famà; C Ciardullo; M Greco; S Cresta; D Piranda; A Holmes; G Fabbri; M Messina; A Rinaldi; J Wang; C Agostinelli; P Piccaluga; M Lucioni; F Tabbò; R Serra; S Franceschetti; C Deambrogi; G Daniele; V Gattei; R Marasca; F Facchetti; L Arcaini; G Inghirami; F Bertoni; S A. Pileri; S Deaglio; R Foà; R Dalla-Favera; L Pasqualucci; R Rabadan; G Gaidano. - In: JOURNAL OF EXPERIMENTAL MEDICINE. - ISSN 0022-1007. - STAMPA. - 0:(In stampa/Attività in corso), pp. 0-0.
ANALYSIS OF THE CODING GENOME OF SPLENIC MARGINAL ZONE LYMPHOMA REVEALS MUTATIONAL ACTIVATION OF NOTCH2 AND OTHER PATHWAYS REGULATING MARGINAL ZONE DIFFERENTIATION
AGOSTINELLI, CLAUDIO;PICCALUGA, PIER PAOLO;PILERI, STEFANO;
In corso di stampa
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-κB, and other pathways deregulated in this disease.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.