Hb F production in stressed erythropoiesis: observations and kinetic models.
The mechanism of stimulation of Hb F in stressed erythropoiesis is examined. Conditions known to produce a transient elevation of F-cells (acute anemia; acute expansion; treatment with cytotoxic compounds) have a common element, the acute kinetic perturbations of erythroid differentiation/maturation they trigger. Cell cycling must be shortened and the total time of differentiation (from BFUe to erythroblast) must be shortened. We propose that F-cells are formed either because of the shortening of erythroid differentiation time or because of shortening of cell cycle of erythroid cells. With the model of shortened differentiation time F-cell formation is attributed to "premature commitment" of progenitors. gamma-gene expression occurs either because chromatin changes that normally inactivate the gamma genes are not completed or because critical divisions in which the gamma genes are normally inactivated are skipped. The model of faster cycling explains F-cell formation by assuming that gamma-gene transcription is activated when the cycle (and especially the duration of G0/G1) of progenitors or erythroblasts falls below a critical time. The proposed models can readily explain the F-cells of the normal adult as the products of random deviation from normal erythroid kinetics. The two models can also explain F-cell formation in chronic erythropoietic stress (chronic hemolytic anemias, patients with hemoglobinopathies). Differences in the degree of F-cell elevation in such patients may reflect differences in the intensity of kinetic perturbation of their erythropoiesis.
G
G
Stamatoyannopoulos
R
R
Veith
R
R
Galanello
T
T
Papayannopoulou
D000740:Anemia / Q000188:drug therapy; D000818:Animals; D001374:Azacitidine / Q000627:therapeutic use; D002453:Cell Cycle; D002454:Cell Differentiation; D003561:Cytarabine / Q000627:therapeutic use; D004920:Erythropoiesis / Q000187:drug effects; D005319:Fetal Hemoglobin / Q000096:biosynthesis*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D006918:Hydroxyurea / Q000627:therapeutic use; D007700:Kinetics; D008954:Models, Biological; D013997:Time Factors; D014158:Transcription, Genetic
D003561:Cytarabine; D005319:Fetal Hemoglobin; D001374:Azacitidine; D006918:Hydroxyurea