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EnglishSplenic 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.
| Titolo: | ANALYSIS OF THE CODING GENOME OF SPLENIC MARGINAL ZONE LYMPHOMA REVEALS MUTATIONAL ACTIVATION OF NOTCH2 AND OTHER PATHWAYS REGULATING MARGINAL ZONE DIFFERENTIATION |
| Autore/i: | 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; AGOSTINELLI, CLAUDIO; PICCALUGA, PIER PAOLO; M. Lucioni; F. Tabbò; R. Serra; S. Franceschetti; C. Deambrogi; G. Daniele; V. Gattei; R. Marasca; F. Facchetti; L. Arcaini; G. Inghirami; F. Bertoni; PILERI, STEFANO; S. Deaglio; R. Foà; R. Dalla Favera; L. Pasqualucci; R. Rabadan; G. Gaidano |
| Autore/i Unibo: | |
| Anno: | Being printed |
| Rivista: | |
| 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. |
| Data stato definitivo: | 2018-03-30T14:47:37Z |
| Appare nelle tipologie: | 1.01 Articolo in rivista |
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