OVERVIEW: MECHANISMS OF THE REGULATION OF HEMOGLOBIN SYNTHESIS AT THE CELLULAR LEVEL

The concept that has emerged from our experiments and those of others is that erythroid stem cells are committed to undergo a program of erythroid differentiation with respect to the ultimate hemoglobin phenotype of their progeny erythrocytes. A clear distinction can be drawn between the switch from Hb A (or Hb F) to Hb C in sheep and the switch from Hb F to adult hemoglobin in humans. The former appears to be regulated in a relatively late erythroid stem cell with characteristics of CFU-E. In contrast, the CFU-E found in adult sheep bone marrow from animals that lack the beta C gene appear to be preprogrammed to produce only adult hemoglobin. Fetal stem cells may be induced to synthesize Hb C within a time frame that is similar to that seen in cultures of adult bone marrow. Thus, a common mechanism modulating the potential for expression of this gene and commitment of erythroid stem cells with respect to Hb C production in progeny erythroblasts seems quite likely. Again fetal CFU-E and BFU-E in animals lacking the beta C gene appear to be, for the most part, committed toward producing erythroblasts making Hb F. Further analysis will be required to determine at exactly which stage of stem cell differentiation this programming occurs and also the factors that are important in modulating the potential for fetal and adult hemoglobin synthesis.