Derangement of DNA Synthesis in Erythroleukaemia. Normal Deoxyuridine Suppression and Impaired Thymidine Incorporation in Bone Marrow Culture

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Abstract
The deoxyuridine (dU) suppression test (i.e., ability of exogenous dU to suppress the incorporation of subsequently added 3H-thymidine into DNA) and the incorporation of 3H-thymidine (3H-TdR) alone without dU were studied in bone marrow cultures from 10 patients with erythroleukemia, 10 patients with vitamin B12/folate-deficient megaloblastic anemia and 10 hematologically normal subjects. Despite a morphological resemblance between megaloblastosis in erythroleukemia and nutritional megaloblastosis, the dU suppression values in erythroleukemia were within the normal range in contrast to abnormal dU suppression in vitamin B12/folate-deficient megaloblastic bone marrows. The incorporation of 3H-thymidine alone was significantly lower in erythroleukemia than in normal or vitamin B12/folate-deficient megaloblastic bone marrows. Autoradiographic studies showed that 3H-TdR labeling indices as well as mean grain count (MGC) of basophilic and polychromatic erythroblasts were significantly lower in erythroleukemia than in normal or vitamin B12/folate-deficient bone marrows. The reduced incorporation of 3H-TdR in erythroleukemia erythroblasts was probably not due to a deficiency of the salvage pathway enzyme, thymidine kinase, since MTX [methotrexate] (10-5 M), which blocks the de novo pathway of thymine-DNA synthesis, enhanced the incorporation of 3H-TdR into erythroblasts in erythroleukemia as well as in normal bone marrows. A high intracellular pool of thymidine-triphosphate (dTTP) due to defective DNA synthesis may allosterically inhibit thymidine kinase and 3H-TdR incorporation.