Reactivation of fetal hemoglobin in thalassemia and sickle cell disease

被引:2
|
作者
Eridani, Sandro [1 ]
Avemaria, Francesca [1 ]
Mosca, Andrea [1 ]
机构
[1] Univ Milan, Dipartimento Fisiopatol Med Chirurg & Trapianti, Milan, Italy
关键词
sickle cell disease; hemoglobin F; determinants; inducers;
D O I
10.4081/thal.2014.2196
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Considerable attention has been recently devoted to mechanisms involved in the perinatal hemoglobin switch, as it was long ago established that the survival of fetal hemoglobin (HbF) production in significant amount can reduce the severity of the clinical course in severe disorders like beta-thalassemia and sickle cell disease (SCD). For instance, when beta-thalassemia is associated with hereditary persistence of fetal hemoglobin (HPFH) the disease takes a mild course, labeled as thalassemia intermedia. The same clinical amelioration occurs for the association between HPFH and SCD. As for the mechanism of this effect, some information has been obtained from the study of natural mutations at the human beta-globin locus in patients with increased HbF, like the Corfu thalassemia mutations. Important evidence came from the discovery that drugs capable of improving the clinical picture of SCD, like decitabine ad hydroxycarbamide, are acting through the reactivation, to some extent, of HbF synthesis. The study of the mechanism of action of these compounds was followed by the identification of some genetic determinants, which promote this event. In particular, among a few genetic factors involved in this process, the most relevant appears the BCL11A gene, which is now credited to be able to silence gamma-globin genes in the perinatal period by interaction with several erythroid-specific transcription factors and is actually considered as a barrier to HbF reactivation by known HbF inducing agents. Epigenetics is also a player in the process, mainly through DNA demethylation. This is certified by the recent demonstration that hypomethylating agents such as 5-azacytidine and decitabine, the first compounds used for HbF induction by pharmacology, act as irreversible inhibitors of demethyltransferase enzymes. Great interest has also been raised by the finding that several micro-RNAs, which act as negative regulators of gene expression, have been implicated in the progression of globin gene expression and, particularly, in the reactivation of gamma-globin gene expression associated with increased HbF synthesis. Probably, this reactivation is achieved by post-transcriptional inhibition of BCL11A expression. Finally, attention is presently focused on a recently discovered BCL11A enhancer, essential for erythroid expression of BCL11A, which might become a therapeutic target for genome engineering in the beta-hemoglobinopathies as its disruption affects only the erythropoietic lineage, without hurting other cell or tissue compartments.
引用
收藏
页码:55 / 61
页数:7
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