HEMOGLOBIN SWITCHING IN HUMANS IS ACCOMPANIED BY CHANGES IN THE RATIOOF THE TRANSCRIPTION FACTORS, GATA-1 AND SP1

Background: Understanding the mechanism of developmental regulation of hemoglobin switching has scientific as well as clinical relevance bec ause of the influence of fetal hemoglobin (HbF) production in adulthoo d on the clinical manifestation of thalassemia and sickle cell anemia. We have previously found that the normal developmental patterns of gl obin gene expression are recapitulated in an experimental system of pr imary cultures that support differentiation of erythroid progenitors. We further found that high activities of the transcriptional activator s, GATA-1 and SP1, are associated with normal adult erythroid differen tiation. Materials and Methods: In the present work, we have studied t he activities of GATA-1 and SP1 during differentiation of cultured ery throid progenitors derived from cord blood and from fetal livers, as w ell as from beta 0-thalassemia patients. Results: The results showed h igh GATA-1 binding activity and very low SP1 activity in the fetal liv er cultures. This pattern was in contrast to cultures derived from nor mal adult peripheral blood, in which both GATA-1 and SP1 activities we re high. Cord blood cultures showed an additive combination of ''adult '' and ''fetal'' patterns. The progenitors derived from a beta(0)-thal assemia patient with high HbF production showed ''fetal'' pattern. On the other hand, in cultures of 2 beta(0)-thalassemia patients without high HbF, ''adult'' pattern was observed. Conclusions: In the present work, we show that human fetal and adult erythroid progenitors are dis tinct in their transcription factors, and that the commitment to fetal or adult program occurs at a very early differentiation stage. Our st udies also demonstrate that under anemic stress, recruitment of fetal progenitors may occur in adulthood.