APOPTOSIS MEDIATES AND THYMIDINE PREVENTS ERYTHROBLAST DESTRUCTION INFOLATE-DEFICIENCY ANEMIA

Deficiency of the vitamin folic acid causes pancytopenia by decreasing the production of new blood cells. Although impaired DNA synthesis an d destruction of hematopoietic cells have been implicated, the mechani sm by which folate deficiency decreases blood cell production is uncer tain. An in vitro model of folate-deficient erythropoiesis was develop ed 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 ap optosis, a form of Programmed cell death, after 20-32 h in culture in folate-deficient medium. At the time of apoptosis the cells had differ entiated into the later erythroblast stages and some had begun hemoglo bin synthesis. Addition of either folic acid or thymidine, but not deo xycytidine or inosine, to the folate-deficient medium prevented the ap optosis and permitted proliferation and differentiation of the proeryt hroblasts into reticulocytes. The prevention of apoptosis by thymidine indicates (i) that decreased thymidylate synthesis plays a role in er ythroblast apoptosis and the anemia of folate deficiency and (ii) that DNA cleavage is likely to be a primary event in the apoptosis of fola te-deficient erythroblasts. Apoptosis of erythroblasts in the late sta ges of differentiation leads to decreased erythrocyte production and t o anemia. The increased erythropoietin produced in response to the ane mia increases the number of erythroid progenitor cells in the differen tiation stages preceding those in which the tells undergo apoptosis. T his population shift to earlier stage erythroblasts and proerythroblas ts is characteristic of bone marrows of individuals with folate defici ency anemia.