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.
In corso di stampa
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.
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
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/122696
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