Clinical Application of Epigenetic Modifier Mutations in Myeloma

Epigenetic deregulation is one of the key mechanisms leading to the development of multiple myeloma (MM). While one of the most commonly discussed mechanisms is the deregulation of MMSET by the t(4;14); recent studies have identified a range of other mechanisms that exert important effects and are also potentially amenable to therapy. Methylation patterns are important in MM progression and are characterized by global hypomethylation and gene specific hypermethylation. Interestingly, while this pattern is globally true, the etiologic variants of MM have distinct patterns arguing for their pathologic relevance of acquired methylation change. Identifying epigenetic mutations in MM has proven difficult because of their low frequency but recently a set of key mutated driver genes has been identified, which include a number of important epigenetic genes, of which are therapeutically tractable. RNA splicing has been identified as an important mechanism in AML/MDS but it is also important in MM. SF3B1 mutation occurs at lower frequency but by analogy are also potential therapeutic targets. Furthermore, abnormal splice patterns are more common than can be explained by mutation alone consistent with their being other events, which impact this pathway making it more relevant as a therapeutic target. The analysis of the coding sequence of MM has yielded many potential targets but little work has been done to date to characterize the non-coding sequences. A feature of the non-coding MM genome pointing to a key tractable epigenetic mechanism is structural genomic rearrangement that involves superenhancers. The etiologic translocations that involve the immunoglobulin gene superenhancers are the prime examples of this mechanism and it is now realized that other genes also contain superenhancers that are recurrently involved in structural events. The net results of such structural rearrangement is altered gene expression mediated by transcriptional deregulation making it a key therapeutic target in MM. Another feature of the non-coding sequence that can be used to define targetable mutations is the identification of mutations within non-coding RNA. Despite having looked for recurrent events within these genomic variants we haven't as yet been successful in identifying a key variant. Targeting epigenetic variables in MM is likely to be a growing therapeutic area beyond the use of histone deacetylase inhibitors already approved for use in MM. We can learn a lot about how to use these agents from the work already being done in AML/MDS aimed at manipulating these pathways. Targeting methylation status with hypomethylating agents is possible but is not without risk in MM, given the clinical methylation patterns we have identified. Given the prevalence of transcriptional deregulation in MM the development agents aimed at manipulating superenhancers such as bromodomain inhibitors could be of particular relevance. However, in MM it will be essential to use epigenetic agents within the correct biological context to maximize their clinical value. This approach will require the development of greater biological knowledge that is translated into diagnostic testing strategies, which identify the cases where there is the greatest likelihood of having a clinical impact.