Evidence for a clonal model for hemoglobin switching.

The ontogenic switch from fetal to adult hemoglobin could be due to gradual replacement of fetal by adult erythroid progenitor cells, each with unique potential hemoglobin expression programs. We have studied globin synthesis in single colonies derived from the BFU-E of human newborn infants and rhesus monkey fetuses, both at the time of the switch. In the 140-day rhesus fetal colonies, beta synthesis ranged from 8% to 44% of (beta + gamma) in 47 colonies. When fetal colonies were arbitrarily defined as those with below 26% beta, and adult colonies those with above 26% beta, we predicted that there would be 12 adult colonies; 14 were observed. The rhesus fetal results were compatible with the presence of two or more classes of progenitors within the population seen at the time of the switch. In the human newborn study, the number of colonies increased fourfold from day 14 to day 21 in culture. beta synthesis also increased. These increases occurred even in cultures from which red, well-hemoglobinized colonies were completely removed as they appeared. New cohorts of late-appearing colonies were derived from immature progenitors. The early colonies showed correlation of G gamma and beta synthesis, but the late colonies did not show this correlation. We had found the latter pattern previously in adult, fetal-like colonies. Thus fetal progenitors in man have high levels of Hb F and G gamma, with correlation of these parameters at the level of single-progenitor-derived colonies; these fetal progenitors are found in fetuses and newborns. Adult, fetal-like progenitors have lower levels of Hb F and G gamma, without any correlation between the levels of each. The adult progenitors appear in newborn infants as the switch occurs, and they are the only class found in adults. Our observations in the simian and human studies support a clonal model for hemoglobin switching.