Decreased expression of fetal hemoglobin around the time of birth represents the defining mechanism in the clinical manifestation of sickle-cell and beta-thalassemia syndromes. Therefore, prevention or reversal of that process represents a major clinical goal for the treatment of those diseases. An ongoing interest of the laboratory involves the study of signal transduction cascades and growth among fully committed erythroid cells as a method of increasing levels of fetal hemoglobin in adult humans. In this context, we developed a standard experimental assay of cultured human erythroid progenitor cells obtained from normal volunteers as well as patients with hemoglobinopathies to identify cytokines capable of modulating erythroid growth and fetal hemoglobin production during adult erythropoiesis. Stem cell factor (SCF) was identified as having significant effects upon erythroid growth and fetal hemoglobin production even among committed proerythroblasts. That approach led to the discovery that TGF-beta, SCF and Erythropoietin act in concert to increase fetal hemoglobin production. Those increases were pancellular, and resulted in production of HbF to levels that may be sufficient to reverse the sickle phenotype in vivo. Efforts have begun to determine the molecular mechanisms responsible for the cytokine effects and to correlate those findings in vivo using clinical samples from patients with hemoglobinopathies.
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