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Imbalance in the Nucleotide Pools of Myeloid Leukemia Cells and HL-60 Cells: Correlation with Cell-Cycle Phase, Proliferation, Differentiation, and Transformation¹

Central Laboratory of the Netherlands Red Cross Blood Transfusion Service, Laboratory for Experimental and Clinical Immunology of the University of Amsterdam [D. d. K., M. d. B., D. R.] and Children's Hospital, Het Emma Kinderziekenhuis, [W. A. H., A. H. v. G.] Amsterdam, The Netherlands

Myeloblasts from the blood of patients with chronic myeloid leukemia (CML) in a blastoid crisis were shown to have an imbalance in the ribonucleotide pools compared with normal blood neutrophils. This imbalance includes decreased ratios of purine:pyrimidine, adenine:guanine, and uracil:cytosine nucleotides as well as an increased relative concentration and a changed composition of the uridine diphosphate (UDP) sugars, with relatively more UDP-N-acetylhexosamines. Similar, more prominent deviations were found in HL-60 promyelocytic leukemia cell line cells. We have used HL-60 cells to investigate the relationships between these changes in the ribonucleotide pools and myelocyte proliferation, maturation, and/or transformation to the malignant state.

When HL-60 cells were separated by elutriation centrifugation into fractions enriched in G₁, S phase, or G₂ + M, we found only differences in the amount of nucleotides per cell (G₂ + M > S phase > G₁) corresponding with the increase in cell volume but not in the qualitative composition of the nucleotides. Therefore, throughout this study, the nucleotide content of all cells was calculated per unit of cell volume.

When HL-60 cells were induced to myeloid differentiation with dimethyl sulfoxide, proliferation stopped after 3 days. After 6 days, 70–90% of the cells had matured into cells capable of nitro blue tetrazolium reduction upon stimulation with phorbol myristate acetate. During the maturation process, the mean volume of the HL-60 cells decreased, and the nucleotide content and the purine:pyrimidine and adenine:guanine nucleotide ratios increased. The composition of the UDP sugars changed dramatically, with a decrease of UDP-N-acetylhexosamines and an increase of UDP-hexoses. Similar changes were detected in HL-60 cells that stopped proliferating without dimethyl sulfoxide-induced maturation, except that the UDP sugar composition showed an increase of UDP-N-acetylhexosamines and a decrease of UDP-hexoses.

Careful examination of these results indicates that the decreased ratio of purine:pyrimidine nucleotides and the decreased ratio of uracil:cytosine nucleotides observed in CML myeloblasts may be regarded as specific changes caused by transformation of myelocytes to the malignant state. The increased amount of UDP-N-acetylhexosamines and total UDP sugars in the CML cells may also be connected with the transformation process. All other deviations in the nucleotide pattern of transformed myelocytes in comparison to that of mature, normal neutrophils can be explained by the state of proliferation and/or immaturity of CML myeloblasts and HL-60 cells. The abnormal UDP sugar concentrations in CML cells form a rationale for the use of D-glucosamine as cytostatic drug, although not specifically for transformed cells.

¹ This study was financially supported by grant number AUKC-EMMA-81-5 from Het Koningin Wilhelmina Fonds, Organization for the Fight Against Cancer, Amsterdam, The Netherlands.

² To whom requests for reprints should be addressed, at % Publication Secretariat, Central Laboratory of the Netherlands Red Cross Blood Transfusion Service, P.O. Box 9406, 1006 AK Amsterdam, The Netherlands.

Received 3/25/86. Revised 12/ 9/86. Accepted 12/11/86.

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