Increased HbF in adult life

Abstract

Considerable advances have been made recently in our understanding of globin gene expression, its developmental regulation and the altered patterns in various inherited and acquired disorders. Each advance has revealed a new layer of complexity and as many questions remain as have been answered. Adult levels of HbF are clearly under genetic control but the number and nature of these genetic factors, either within or outside of the beta-globin gene cluster, remain to be determined. Many of the conditions resulting in increased HbF in adult life appear to involve an increased erythropoietic drive which results in a higher proportion of erythroid progenitor cells activating their inherent ability to synthesise low amounts of HbF. The mechanism by which this is achieved remains unknown but these observations have been confirmed in a number of experimental systems and have led to the use of mildly cytotoxic drugs to increase the HbF levels in sickle cell anaemia. Similarly, the clinical observation that infants of diabetic mothers show delayed fetal to adult haemoglobin switching has led to the development of butyrate derivatives to increase adult HbF levels. Analysis of the HPFH mutations has so far been largely limited to the deletion conditions and the gamma-gene promoter base substitutions. In neither case is there a complete explanation which can account for the raised adult HbF level characteristic of these conditions. Rather, they seem to demonstrate the complexity, and perhaps redundancy, of the mechanisms which control haemoglobin production. Both conditions show features which are consistent with competition between the gamma- and beta-genes in adult life, an interpretation which is apparently at odds with the 'autonomous' regulation of the gamma-genes in adult transgenic mice. Analysis of further transgenic mice, including ones bearing HPFH mutations, may help resolve this apparent contradiction and may provide suitable material to examine the in vivo protein-DNA interactions in this region.