Marginal zone lymphomas are interesting in their pathogenesis, with several of the extranodal types related to chronic infections, such as H. pylori, B. burgdorferi, and C. psittaci. Splenic marginal zone lymphoma (SMZL) shows some linkage to hepatitis C infection, but only in a minority of cases as the incidence is low even in regions where hepatitis C infection is relatively prevalent. The molecular events underlying this generally indolent illness are incompletely characterized. Uncommonly, for a low-grade lymphoma, alkylating agents are relatively ineffective treatment, which is possibly linked to the high rates of TP53 deletion observed. The therapeutic approaches most often used are rituximab, alone or in combination with cytotoxic agents, or splenectomy. No potentially helpful targeted agents have been suggested until now, as molecular characterization of the pathobiology of SMZL has been impeded by the relative rarity of the disease.
A collaborative group composed of researchers from the University of Eastern Piedmont in Novara, several other Italian centers, and the group at Columbia University, and another collaborative group made up of researchers from the University of Michigan and other North American centers used whole-genome sequencing to identify patterns of mutation in a small number of cases. The Italian group also used copy-number analysis to highlight the major areas of gain or loss of chromosomal DNA. Both groups used Sanger sequencing to confirm their findings in a larger cohort; the results are broadly similar. The most notable finding was the frequent mutation in the NOTCH-2 gene, in a region that results in loss of the C-terminal PEST domain, thereby impairing proteosomal degradation of the truncated protein. This abnormality was present in 20 to 25 percent of SMZL cases, but very few other lymphoma types, and is thought to result in upregulation of the NOTCH pathway. Interestingly, in a smaller number of cases, the Italian group also found genetic lesions in other components of the NOTCH pathway, such as NOTCH-1, SPEN, and DTX1, suggesting convergence of the mechanisms of pathogenesis. They also identified less frequent mutations in genes regulating chromatin remodeling and transcription, and B-cell receptor signaling, as have been described in other low-grade B-cell lymphomas.
There was an interesting divergence between the two studies when the clinical significance of the NOTCH-2 mutation was investigated, with the Italian group concluding that mutant cases had a better overall survival, but the Michigan group finding that mutant cases were more likely to undergo recurrence, transformation, and fatal progression. It seems likely that selection bias influenced these findings, but there is clearly more work to do in understanding the significance of mutations of this gene in the progression of lymphoma.
In Brief
The NOTCH pathway shows a high degree of evolutionary conservation and is responsible for regulating many developmental decisions, such as hemopoietic lineage identity, as well as differentiation and tissue homeostasis. This diverse developmental regulation includes the formation of the B-cell marginal zone in lymphatic tissue and the maturation of the antibody repertoire. Apparently, NOTCH-2 is not sufficient for malignant transformation, since patients with the Hajdu-Cheney syndrome, which is caused by NOTCH-2 germline mutations similar to those described in SMZL, do not show an increased incidence of lymphoma, although they do experience severe progressive bone loss. The frequent occurrence of activating mutations in SMZL does, however, suggest that to prevent clonal escape the NOTCH pathway might be a target for intervention perhaps in combination with inhibitors of the other relevant pathways. In this context, use of inhibitors of the NF-κB pathway or of B-cell receptor signaling would seem a logical therapeutic approach in combination with a NOTCH inhibitor. Given the generally slow pace of progression, it may be that such an approach could be successful in controlling the disease over long periods of time.
Competing Interests
Dr. Johnson indicated no relevant conflicts of interest.
