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immature committed erythroid precursors (BFU-e) that retain the ability to produce HbF2.Multiple beneficial effects of hydroxyurea for SCA. (1) Fetal hemoglobin induction through soluble guanylyl cyclase activation and altered erythroid kinetics; (2) lower neutrophil and reticulocyte counts from ribonucleotide reductase inhibition and marrow cytotoxicity; (3) decreased adhesiveness and improved rheology of circulating neutrophils and reticulocytes; (4) reduced hemolysis through improved erythrocyte hydration, macrocytosis, and reduced intracellular sickling; and (5) Nitric oxide (NO) release with potential local vasodilatation and improved vascular response. Illustration courtesy of Alice Y. Chen.xxxviii.Proposed mechanisms of fetal hemoglobin modulation via hydroxycarbamide treatment (adapted from Stamatoyannopoulos, G. Experimental Hematology 2005; 33: 259–271). (A) Normal fetal and adult hemoglobin are produced by cells from the same lineage, i.e. hemoglobin switching occurs through a change in transcription program within the same cell. A change in transcription program occurs with erythropoietic differentiation, from one that predominantly supports γ globin expressionto one that supports only β globin expression. FC represents the progeny of erythroid progenitor cells that terminate early before the change in transcription program occurs. Two plausible mechanisms of HbF modulation have emerged from biological studies of the QTLs. (B) Direct effect on γ globin gene expression (BCL11A is proposed as a developmental stage-specific repressor); and (C) Indirect via perturbation of kinetics of erythropoiesis—HMIP 2 contains a distal regulatory locus
that controls MYB expression, whose levels affect differentiation of erythropoiesis. An accelerated erythropoiesis (mimicking stress erythropoiesis) leads to the release of more progenitor cells that are still syntesizing significant amounts of HbF.b.Stem Cells and Regenerative Biology