NOTCH2 Mutations in Marginal Zone Lymphoma.

Notch2 is a membrane receptor and transcription factor that is indispensable for marginal zone cell differentiation. Also, marginal zone cell lymphomas express increased levels of Notch2 when compared with other B-cell lymphomas. Of interest, activating mutations have previously been described for Notch1, a homologous transcription factor which is important for T-cell differentiation, in up to 50% of cases of acute T-lymphoblastic leukemia, and are thought to contribute to leukemogenesis. We therefore investigated whether activating mutations in the NOTCH2 gene could be identified, especially in marginal zone lymphoma (MZL). We analyzed 41 cases of MZL and 28 other B-cell lymphomas cases for the presence of potentially activating mutations in exons 26, 27 and 34 of the NOTCH2 gene. These exons code for the heterodimerization and the C-terminal transcriptional activation domains. We identified four cases with mutations among the MZL cases, but none in the other B-cell lymphoma cases. Mutations were found in two cases of splenic marginal zone lymphoma and two cases of extranodal marginal zone lymphoma of MALT type, respectively. To investigate whether elevated Notch2 expression in most of the other marginal zone lymphomas, as investigated by quantitative RT-PCR, was due to structural changes within the NOTCH2 locus, FISH analysis was performed. FISH analysis did not reveal structural changes of the NOTCH2 locus in any of the MZL cases. In conclusion, we have shown potentially oncogenic NOTCH2 mutations in 10% of MZL. It remains to be shown whether elevated Notch2 expression in most MZL can be caused by as yet other disease mechanisms.