Mechanism of action of hypomethylating agents in myelodysplastic syndromes

Abstract

DNA hypermethylation is an important process in oncogenesis, especially in patogenesis of
myelodysplastic syndrome (MDS). DNA hypomethylation is associated with inducing reexpression
of epigenetically silenced suppressor genes. Two hypomethylating agents are currently
used in the treatment of patients with MDS: azacitidine and decitabine. Therapy with those
drugs, administered in low doses, results in DNA demethylation through the inhibition of
DNA methyltransferase. It is confirmed in randomized trials, that hypomethylating drugs improve outcome of selected patients with MDS. Azacitidine is proved to prolong survival of
patients with MDS, and currently is recommended for treatment of patients from the
intermediate and high risk group who are not eligible for allogeneic hematopoietic stem cell
transplantation (allo-HSCT). Hypomethylating agents appear to induce leukemic cell
differentiation and to increase expression of HLA-DR antigens and other leukemia-associated
antigens, which can increase graft versus leukemia effect after allo-HSCT. Detailed mechanism
of action of hypomethylating agents is not known. Clinical response is probably related to
cellular metabolism of those drugs. Molecular biomarkers should be found to predict therapy
responses and patients outcome.