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.

The coding genome of splenic marginal zone lymphoma: activation of NOTCH2 and other pathways regulating marginal zone development / D., Rossi; V., Trifonov; M., Fangazio; A., Bruscaggin; S., Rasi; V., Spina; S., Monti; T., Vaisitti; F., Arruga; R., Fama; C., Ciardullo; M., Greco; S., Cresta; D., Piranda; A., Holmes; G., Fabbri; M., Messina; A., Rinaldi; J., Wang; C., Agostinelli; P. P., Piccaluga; M., Lucioni; F., Tabbo; R., Serra; S., Franceschetti; C., Deambrogi; G., Daniele; V., Gattei; Marasca, Roberto; F., Facchetti; L., Arcaini; G., Inghirami; F., Bertoni; S. A., Pileri; S., Deaglio; R., Foa; R., Dalla Favera; L., Pasqualucci; R., Rabadan; G., Gaidano. - In: JOURNAL OF EXPERIMENTAL MEDICINE. - ISSN 0022-1007. - STAMPA. - 209:(2012), pp. 1537-1551. [10.1084/jem.20120904]

The coding genome of splenic marginal zone lymphoma: activation of NOTCH2 and other pathways regulating marginal zone development

MARASCA, Roberto;
2012-01-01

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.
209
1537
1551
The coding genome of splenic marginal zone lymphoma: activation of NOTCH2 and other pathways regulating marginal zone development / D., Rossi; V., Trifonov; M., Fangazio; A., Bruscaggin; S., Rasi; V., Spina; S., Monti; T., Vaisitti; F., Arruga; R., Fama; C., Ciardullo; M., Greco; S., Cresta; D., Piranda; A., Holmes; G., Fabbri; M., Messina; A., Rinaldi; J., Wang; C., Agostinelli; P. P., Piccaluga; M., Lucioni; F., Tabbo; R., Serra; S., Franceschetti; C., Deambrogi; G., Daniele; V., Gattei; Marasca, Roberto; F., Facchetti; L., Arcaini; G., Inghirami; F., Bertoni; S. A., Pileri; S., Deaglio; R., Foa; R., Dalla Favera; L., Pasqualucci; R., Rabadan; G., Gaidano. - In: JOURNAL OF EXPERIMENTAL MEDICINE. - ISSN 0022-1007. - STAMPA. - 209:(2012), pp. 1537-1551. [10.1084/jem.20120904]
D., Rossi; V., Trifonov; M., Fangazio; A., Bruscaggin; S., Rasi; V., Spina; S., Monti; T., Vaisitti; F., Arruga; R., Fama; C., Ciardullo; M., Greco; S., Cresta; D., Piranda; A., Holmes; G., Fabbri; M., Messina; A., Rinaldi; J., Wang; C., Agostinelli; P. P., Piccaluga; M., Lucioni; F., Tabbo; R., Serra; S., Franceschetti; C., Deambrogi; G., Daniele; V., Gattei; Marasca, Roberto; F., Facchetti; L., Arcaini; G., Inghirami; F., Bertoni; S. A., Pileri; S., Deaglio; R., Foa; R., Dalla Favera; L., Pasqualucci; R., Rabadan; G., Gaidano
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