Some Aspects of Erythropoietic Cell Proliferation in Erythroleukaemia

Abstract

Cytophotometric-autoradiographic investigations on erythropoiesis in erythroleukaemia indicate: (1) the decreased labelling index of erythroblasts is explained by an increased percentage of these cells in G₁;(2) ‘megaloblastoid’ basophilic erythroblasts show a more pronounced decrease of their fraction in DNA synthesis than morphological normal cells; (3) ‘megaloblastoid’ early polychromatic normoblasts represent a non-proliferating cell population, and (4) the detected disturbance of cell proliferation – eventhough temporary – can bereversed.

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

“…The significant reduc tion of both labelling indices and MGC of erythroblasts in erythroleukaemia (table IV) suggest that mean 3H-TdR incorporation into DNA per DNA-synthesizing ervthroblast (S-phase cell) would be lower in eryth roleukaemia than in normal or vitamin B)2/ folate-deficient megaloblastic bone mar rows. The results are consistent with those of previous investigators who reported a marked decrease in the fraction of DNAsynthesizing cells among basophilic and ear ly polychromatic erythroblasts in erythro-leukaemia bone marrow [11,22,24,26], This defect appeared to be more pron ounced in the erythroblasts with 'megaloblastoid' appearance, a large fraction of which constituted a non-proliferating cell popula tion [22]. Combined cytophotometric and autoradiographic studies further showed that this abnormality was mainly due to an abnormal accumulation of cells in GO or G1 phase, and the presence of 'U' cells, which were unlabelled with • ' !H-TdR had DNA content between diploid (2c) to tetraploid (4c) values [3,22,24,26].…”

“…The results are consistent with those of previous investigators who reported a marked decrease in the fraction of DNAsynthesizing cells among basophilic and ear ly polychromatic erythroblasts in erythro-leukaemia bone marrow [11,22,24,26], This defect appeared to be more pron ounced in the erythroblasts with 'megaloblastoid' appearance, a large fraction of which constituted a non-proliferating cell popula tion [22]. Combined cytophotometric and autoradiographic studies further showed that this abnormality was mainly due to an abnormal accumulation of cells in GO or G1 phase, and the presence of 'U' cells, which were unlabelled with • ' !H-TdR had DNA content between diploid (2c) to tetraploid (4c) values [3,22,24,26]. The cytokinetic abnormalities of erythroblasts particularly 'megaloblastoid' cells simulated those re ported in leukaemic myeloblasts [2,20], These and other lines of investigations sug gested that the abnormal growth and prolif eration of erythroblasts in erythroleukaemia probably resulted from neoplastic transfor mation of a stem cell common to both erythroid and granulocytic series [5,12,18,19], It is possible that the impaired DNA metabolism in erythroid precursor cells spe cially 'megaloblastoid' erythroblasts in ery throleukaemia is a characteristic feature, fundamental to the neoplastic or leukaemic nature of these cells.…”

“…dTMP, which, after a sequence of phosphorylation forms dTTP and is uti lized for DNA synthesis, is in turn produced either by de novo synthesis from carbamylasparate or by phosphorylation of exogen ous thymidine by the salvage pathway. The two alternative pathways of thymidylate synthesis, the de novo and the salvage path ways, are interrelated by a common end product, dTTP which exerts a regulatory in fluence on both pathways by a feedback in hibition [17], This also accounts for the re ciprocity of the two pathways [9], In defi ciency of vitamin B12 and folate or in the presence of folate antagonists such as MTX, the impairment of the de novo pathway leads to increased activity of the salvage en zyme, thymidine kinase [16,22], which in turn promotes increased incorporation of exogenous thymidine into DNA. In con trast, the megaloblastoid erythroblasts in ery throleukaemia marrows showed reduced incorporation of exogenous sH-TdR as compared to normal as well as vitamin B12/ folate-deficient megaloblastic bone mar rows.…”