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Blood, 1 November 2000, Vol. 96, No. 9, pp. 3249-3255
RED CELLS
Apoptosis in megaloblastic anemia occurs during
DNA synthesis by a p53-independent,
nucleoside-reversible mechanism
Mark J. Koury,
James O. Price, and
Geoffrey G. Hicks
From the Departments of Medicine, Pathology, and
Microbiology and Immunology, Vanderbilt University and Department of
Veterans Affairs Medical Centers, Nashville, TN.
Deficiency of folate or vitamin B12 (cobalamin)
causes megaloblastic anemia, a disease characterized by pancytopenia
due to the excessive apoptosis of hematopoietic progenitor cells.
Clinical and experimental studies of megaloblastic anemia have
demonstrated an impairment of DNA synthesis and repair in hematopoietic
cells that is manifested by an increased percentage of cells in the DNA
synthesis phase (S phase) of the cell cycle, compared with normal hematopoietic cells. Both folate and cobalamin are required for
normal de novo synthesis of thymidylate and purines. However, previous
studies of impaired DNA synthesis and repair in megaloblastic anemia
have concerned mainly the decreased intracellular levels of thymidylate
and its effects on nucleotide pools and misincorporation of uracil into
DNA. An in vitro model of folate-deficient erythropoiesis was used to
study the relationship between the S-phase accumulation and apoptosis
in megaloblastic anemia. The results indicate that folate-deficient
erythroblasts accumulate in and undergo apoptosis in the S phase when
compared with control erythroblasts. Both the S-phase accumulation and
the apoptosis were induced by folate deficiency in erythroblasts from
p53 null mice. The complete reversal of the S-phase
accumulation and apoptosis in folate-deficient erythroblasts required
the exogenous provision of specific purines or purine nucleosides as
well as thymidine. These results indicate that decreased de novo
synthesis of purines plays as important a role as decreased de
novo synthesis of thymidylate in the pathogenesis of megaloblastic anemia.
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