The application of gene profiling to hematologic malignancies has the potential to provide prognostic information while simultaneously guiding therapy. For example, the molecular signature of the activated B-cell subtype (ABC) of diffuse large B-cell lymphoma (DLBCL) in contrast to the germinal center subtype (GC) is characterized by increased expression of genes associated with activation of the NF-κB pathway.1 Notably, patients with the ABC form of DLBCL have a substantially worse prognosis than their GC counterparts and are more likely to respond to agents (e.g., bortezomib) that interrupt NF-κB signaling. More recently, evidence has emerged that in addition to such genetic profiles, epigenetic signatures could also have important prognostic and possibly therapeutic implications. In this context, a recent study demonstrated that patients with acute myelogenous leukemia exhibiting specific gene expression profiles may be segregated according to their DNA methylation patterns.2
Until now, parallel studies had not been performed on patients with mantle cell lymphoma (MCL), a form of non-Hodgkin lymphoma associated with specific genetic abnormalities (e.g., t(11:14) translocation, cyclin D1 overexpression, etc.). However, this situation has now changed with the report by Leshchenko et al. from the Parekh laboratory at Albert Einstein Medical Center in New York. These investigators analyzed genome-wide methylation in MCL patients using the HELP assay and identified multiple genes, including CD37, exhibiting aberrant methylation patterns (i.e., either hypo- or hyper-methylation) associated with expected changes in mRNA levels. Interestingly, exposure of MCL cell lines to hypomethylating agents (i.e., decitabine) reversed the aberrant methylation and greater-than-additive effects were observed when decitabine was combined with an HDAC inhibitor (vorinostat). In addition, targeting CD37 with an immunopharmaceutical resulted in a striking loss of viability of MCL cells. The authors concluded that in MCL aberrantly methylated genes can be targeted with therapeutic intent.
In Brief
The results of this study have potentially important implications for MCL and possibly other hematologic malignancies. In the distant past, prognostic information was derived primarily from morphologic and anatomic criteria. Subsequently, the presence or absence of specific chromosomal abnormalities or mutant tyrosine kinases were incorporated into the equation, and in some cases, such as AML with FLT3 mutations, the oncoprotein has been targeted directly. Recently, gene profiling has revealed specific disease subcategories in which prognosis may be independent of morphologic features, chromosomal abnormalities, or the presence of mutant proteins. The significance of the present as well as recent related reports is that epigenetic abnormalities, particularly methylation-induced gene silencing, may provide yet another level of disease categorization and segregation. In the case of MCL, the concept of combining epigenetic strategies involving hypomethylating agents and HDAC inhibitors, a strategy that has shown promise in other disorders (e.g., AML and MDS), has been minimally explored, but based on the results of the Leshchenko report, certainly warrants further investigation into this disorder. Clearly, future prospective studies will be necessary to validate the prognostic and potentially therapeutic significance of aberrant methylation profiles in MCL, a task that now seems to be eminently feasible.
