Apoptosis mediates and thymidine prevents erythroblast destruction in folate deficiency anemia.
Deficiency of the vitamin folic acid causes pancytopenia by decreasing the production of new blood cells. Although impaired DNA synthesis and destruction of hematopoietic cells have been implicated, the mechanism by which folate deficiency decreases blood cell production is uncertain. An in vitro model of folate-deficient erythropoiesis was developed by using proerythroblasts isolated from folate-deficient mice that were infected with Friend leukemia virus. Proerythroblasts from folate-deficient mice had one-tenth the total folate as did proerythroblasts from control mice. The folate-deficient proerythroblasts underwent apoptosis, a form of programmed cell death, after 20-32 h in culture in folate-deficient medium. At the time of apoptosis the cells had differentiated into the later erythroblast stages and some had begun hemoglobin synthesis. Addition of either folic acid or thymidine, but not deoxycytidine or inosine, to the folate-deficient medium prevented the apoptosis and permitted proliferation and differentiation of the proerythroblasts into reticulocytes. The prevention of apoptosis by thymidine indicates (i) that decreased thymidylate synthesis plays a role in erythroblast apoptosis and the anemia of folate deficiency and (ii) that DNA cleavage is likely to be a primary event in the apoptosis of folate-deficient erythroblasts. Apoptosis of erythroblasts in the late stages of differentiation leads to decreased erythrocyte production and to anemia. The increased erythropoietin produced in response to the anemia increases the number of erythroid progenitor cells in the differentiation stages preceding those in which the cells undergo apoptosis. This population shift to earlier stage erythroblasts and proerythroblasts is characteristic of bone marrows of individuals with folate deficiency anemia.
Koury
M J
MJ
Department of Medicine, Vanderbilt University, Nashville, TN 37232.
Horne
D W
DW
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001853:Bone Marrow / Q000473:pathology; D004249:DNA Damage; D015672:Erythroid Precursor Cells / Q000166:cytology*; D005260:Female; D005494:Folic Acid Deficiency / Q000473:pathology / Q000503:physiopathology*; D006410:Hematopoiesis / Q000187:drug effects; D051379:Mice; D010198:Pancytopenia / Q000473:pathology / Q000503:physiopathology*; D013936:Thymidine / Q000494:pharmacology*
D013936:Thymidine