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Apoptosis of late-stage erythroblasts in megaloblastic anemia: association
with DNA damage and macrocyte production
MJ Koury, DW Horne, ZA Brown, JA Pietenpol, BC Blount, BN Ames, R Hard and ST Koury
Department of Internal Medicine, Vanderbilt University and Veterans
Administration Medical Centers, Nashville, TN 37232-6305, USA.
An in vitro model of folate-deficient erythropoiesis has been developed
using proerythroblasts isolated from the spleens of Friend virus- infected
mice fed an amino acid-based, folate-free diet. Control proerythroblasts
were obtained from Friend virus-infected mice fed the same diet plus 2 mg
folic acid/kg diet. Our previous studies showed that, after 20 to 32 hours
of culture in folate-deficient medium with 4 U/mL of erythropoietin, the
folate-deficient proerythroblasts underwent apoptosis, whereas control
erythroblasts survived and differentiated into reticulocytes over a period
of 48 hours. The addition of folic acid or thymidine to the
folate-deficient medium prevented the apoptosis of the folate-deficient
erythroblasts, thereby implicating decreased thymidylate synthesis as the
main cause of apoptosis in the folate-deficient erythroblasts. In the study
reported here, we examined intracellular folate levels, uracil
misincorporation into DNA, p53 and p21 proteins, and reticulocyte formation
in erythroblasts cultured in folate-deficient or control medium. In all
experiments, the folate- deficient erythroblasts cultured in
folate-deficient medium gave results that varied significantly from
folate-deficient erythroblasts cultured in control medium or control
erythroblasts cultured in either folate-deficient or control media.
Folate-deficient erythroblasts cultured in folate-deficient medium had
marked decreases in all coenzyme forms of folate that persisted throughout
culture, increased uracil misincorporation into DNA, persistent
accumulations of p53 and p21, and decreased reticulocyte production but
increased size of individual reticulocytes. A model of folate-deficient
erythropoiesis based on apoptosis of late stage erythroblasts is presented.
This model provides explanations for the clinical findings in megaloblastic
anemia.
Volume 89,
Issue 12,
pp. 4617-4623,
06/15/1997
Copyright © 1997 by The American Society of Hematology
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