The discovery of the inverse relationship between methylation of cytosine residues and gene expression provided an early glimpse of the important role of epigenetic modifications in the regulation of globin gene expression. The use of 5-azacytidine to induce hypomethylation of silenced fetal globin genes to reactivate their expression in adult life heralded a new era in molecular therapy.1 Although the induction of fetal hemoglobin (HbF) by 5-azacytidine was impressive, serious concerns about its potential short- and long-term side effects prevented its widespread use in sickle cell disease and/or β-thalassemia. Interestingly, controversy over the proposed mechanism of induction of HbF by 5-azacytidine led to the identification of hydroxyurea as another chemotherapeutic agent that can activate HbF expression in adult life. A large, multicenter, randomized, placebo-controlled study demonstrated a reduction by about half in vasoocclusive crises and acute chest syndrome in hydroxyurea-treated patients.2 Longer follow-up of patients enrolled in this study demonstrated a survival advantage of treatment with hydroxyurea in sickle cell disease.3
In spite of the remarkable benefits of hydroxyurea in sickle cell disease, approximately half of the treated patients do not respond to this therapy. An earlier study by Koshy et al4 showed that in all patients who did not respond to hydroxyurea, HbF levels increased in response to intravenous decitabine, a new analogue of 5-azacytidine that has more potent hypomethylation activity and a more favorable safety profile. The article by Saunthararajah and colleagues (page 3865) represents an important advance that brings hypomethylation therapy back to center stage. The authors extend their earlier observations and show a more impressive increase in HbF levels following intermittent subcutaneous administration of low-dose decitabine. All 8 patients enrolled in this study had a significant increase in their HbF levels, including those with low baseline HbF levels who failed to respond to hydroxyurea. Such patients would probably be butyrate unresponsive too since a low baseline HbF level appears to predict failure to respond to butyrate.5 Just as importantly, the studies of Saunthararajah et al demonstrate, for the first time, that the observed induction of HbF is associated with decreased methylation at key cytosine residues in the promoters of the γ-globin genes. In addition, this study demonstrates significant improvements in the parameters of red cell adhesion, endothelial damage, and activation of the coagulation pathway following decitabine exposure. The only short-term toxicity that was observed was grade 4 neutropenia in 1 patient and grade 3 neutropenia in 2 others. It is still not clear whether the high HbF levels would persist following long-term subcutaneous therapy with decitabine and what the potential toxicity of such long-term treatment might be. It is also not clear whether decitabine would also be active in β-thalassemia where hydroxyurea has been rather disappointing. Like all good studies, this one raises as many new questions as it answers. Nonetheless, the resurrection of hypomethylation therapy for hemoglobin disorders opens several new avenues of clinical investigation into the potential benefits of new therapeutic agents that target epigenetic modifications that regulate gene expression.