Blood, 15 May 2003, Vol. 101, No. 10, pp. 3762-3762
Therapeutic remodeling of myeloma chromatin
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.
P. Leif Bergsagel
Weill Medical College of Cornell
University
