Multiple myeloma cells dysregulate critical oncogenes and tumor suppressor genes by a number of mechanisms. In addition to genetic changes, there are less well-studied epigenetic changes that can result in the silencing of tumor suppressor genes and contribute to disease progression. These heritable changes are associated with 3 distinct modifications to the DNA and associated chromatin: methylation of cytosines, deacetylation of histones, and methylation of histones. Epigenetic changes represent powerful mechanisms for cancer progression because unlike mutations, they are able to silence not just a single gene but multiple genes in multiple pathways. At the same time, this makes them a very attractive target for anticancer drug development. By inhibiting a single target, one can expect to reactivate the expression of a number of genes whose silencing was critical to the tumor formation and at the same time expect relatively modest effects in nontransformed cells.
The relationship between these 3 epigenetic mechanisms are beginning to be elucidated. In an elegant study using a colon cancer cell line, Vogelstein and colleagues (Cancer Cell. 2003;3:89-95) have demonstrated that the primary event causing gene silencing appears to be aberrant histone methylation, which is followed subsequently by histone deacetylation and cytosine methylation. Agents targeting these processes are being actively developed and investigated in clinical trials.
The first agent to be developed is the cytosine nucleoside analog, 5-aza-2′-deoxycytidine, a potent inhibitor of DNA methylation and an active antileukemic agent. Several agents that inhibit histone deacetylation, including butyrates, valproic acid, SAHA, pyroxamide, depsipeptide, MS-275, and CCI-994, are in clinical trials. In this issue, Nicholas and Constantine Mitsiades and their colleagues (page 4055) provide the first glimpse of these powerful new agents in myeloma. They show that, as with other tumors, in myeloma SAHA is a powerful inducer of p21, growth arrest, and apoptosis. So far we have not seen the development of any histone methyltransferase inhibitors; however, it has recently been discovered that proteins containing a SET domain can act as histone lysine methyl-transferases. Given the flurry of papers describing the structural biology of these domains, it appears likely that specific inhibitors will not be far behind. These agents offer particular promise because they may target a primary event in epigenetic regulation, and in the case of t(4;14) MM with dysregulation of MMSET, a primary genetic event in the pathogenesis of myeloma.
