Abstract
Canine cyclic hematopoiesis is an autosomal recessive disease characterized by regular 11-13-d cycles of the neutrophil, reticulocyte, and platelet counts caused by a defect in regulation of marrow stem cell proliferation. Treatment with lithium abrogates cycling of the cell counts in these grey collie dogs. Aware of the defective lymphopoiesis associated with adenosine deaminase and purine nucleoside phosphorylase deficiencies, we hypothesized that abnormal purine or pyrimidine metabolism might be present in these dogs. Using high pressure liquid chromatography, we measured erythrocyte purine and pyrimidine nucleotide levels and plasma purine and pyrimidine nucleosides and bases in normal and grey collie dogs before and during lithium treatment. During neutropenic periods in the grey collies, erythrocyte ATP, GTP, and UTP levels were significantly elevated. Normal dogs made neutropenic with cyclophosphamide did not show such elevations. Lithium treatment normalized the levels of erythrocyte ATP, GTP, and UTP in the grey collies and eliminated the differences between normal and grey collie nucleotide levels. Plasma thymine levels were markedly increased during neutropenia in the grey collie but were not increased in cyclophosphamide-treated normal dogs. The finding of abnormal concentrations of purine and pyrimidine metabolites in these dogs suggest that a metabolic derangement in purine or pyrimidine metabolism may be the cause of the defective stem cell proliferation in this disease.
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Selected References
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- Adamson J. W., Dale D. C., Elin R. J. Hematopoiesis in the grey collie dog: studies of the regulation of erythropoiesis. J Clin Invest. 1974 Oct;54(4):965–973. doi: 10.1172/JCI107837. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dale D. C., Alling D. W., Wolff S. M. Cyclic hematopoiesis: the mechanism of cyclic neutropenia in grey collie dogs. J Clin Invest. 1972 Aug;51(8):2197–2204. doi: 10.1172/JCI107027. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dale D. C., Graw R. G., Jr Transplantation of allogenic bone marrow in canine cyclic neutropenia. Science. 1974 Jan 11;183(4120):83–84. doi: 10.1126/science.183.4120.83. [DOI] [PubMed] [Google Scholar]
- Dale D. C., Ward S. B., Kimball H. R., Wolff S. M. Studies of neutrophil production and turnover in grey collie dogs with cyclic neutropenia. J Clin Invest. 1972 Aug;51(8):2190–2196. doi: 10.1172/JCI107026. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dunn C. D., Jolly J. D., Jones J. B., Lange R. D. Erythroid colony formation in vitro from the marrow of dogs with cyclic hematopoiesis: interrelationship of progenitor cells. Exp Hematol. 1978 Oct;6(9):701–708. [PubMed] [Google Scholar]
- Dunn C. D., Jones J. B., Jolly J. D., Lange R. D. Cell proliferation of canine cyclic hematopoietic marrow in diffusion chambers. Proc Soc Exp Biol Med. 1978 May;158(1):50–53. doi: 10.3181/00379727-158-40137. [DOI] [PubMed] [Google Scholar]
- Dunn C. D., Jones J. B., Jolly J. D., Lange R. D. Progenitor cells in canine cyclic hematopoiesis. Blood. 1977 Dec;50(6):1111–1120. [PubMed] [Google Scholar]
- Fox R. M., Piddington S. K., Tripp E. H., Dudman N. P., Tattersall M. H. Thymidine sensitivity of cultured leukaemic lymphocytes. Lancet. 1979 Aug 25;2(8139):391–393. doi: 10.1016/s0140-6736(79)90405-7. [DOI] [PubMed] [Google Scholar]
- Gallo R. C., Breitman T. R. The enzymatic mechanisms for deoxythymidine synthesis in human leukocytes. 3. Inhibition of deoxythymidine phosphorylase by purines. J Biol Chem. 1968 Oct 10;243(19):4943–4951. [PubMed] [Google Scholar]
- Gallo R. C., Perry S., Breitman T. R. The enzymatic mechanisms for deoxythymidine synthesis in human leukocytes. I. Substrate inhibition by thymine and activation by phosphate or arsenate. J Biol Chem. 1967 Nov 10;242(21):5059–5068. [PubMed] [Google Scholar]
- Gallo R. C., Perry S. The enzymatic mechanisms for deoxythymidine synthesis in human leukocytes. IV. Comparisons between normal and leukemic leukocytes. J Clin Invest. 1969 Jan;48(1):105–116. doi: 10.1172/JCI105958. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gallo R. C. Synthesis and metabolism of DNA and DNA precursors by human normal and leukemic leukocytes. A summary of recent information. Acta Haematol. 1971;45(3):136–158. doi: 10.1159/000208619. [DOI] [PubMed] [Google Scholar]
- Garrett C., Santi D. V. A rapid and sensitive high pressure liquid chromatography assay for deoxyribonucleoside triphosphates in cell extracts. Anal Biochem. 1979 Nov 1;99(2):268–273. doi: 10.1016/s0003-2697(79)80005-6. [DOI] [PubMed] [Google Scholar]
- Gelfand E. W., Dosch H. M., Hastings B., Shore A. Lithium: a modulator of cyclic AMP-dependent events in lymphocytes? Science. 1979 Jan 26;203(4378):365–367. doi: 10.1126/science.216075. [DOI] [PubMed] [Google Scholar]
- Giblett E. R., Ammann A. J., Wara D. W., Sandman R., Diamond L. K. Nucleoside-phosphorylase deficiency in a child with severely defective T-cell immunity and normal B-cell immunity. Lancet. 1975 May 3;1(7914):1010–1013. doi: 10.1016/s0140-6736(75)91950-9. [DOI] [PubMed] [Google Scholar]
- Giblett E. R., Anderson J. E., Cohen F., Pollara B., Meuwissen H. J. Adenosine-deaminase deficiency in two patients with severely impaired cellular immunity. Lancet. 1972 Nov 18;2(7786):1067–1069. doi: 10.1016/s0140-6736(72)92345-8. [DOI] [PubMed] [Google Scholar]
- Hammond W. P., Adamson J. W., Dale D. C. Canine cyclic haematopoiesis: the effect of endotoxin on erythropoiesis. Br J Haematol. 1982 Feb;50(2):283–294. doi: 10.1111/j.1365-2141.1982.tb01918.x. [DOI] [PubMed] [Google Scholar]
- Hammond W. P., Dale D. C. Cyclic hematopoiesis: effects of lithium on colony-forming cells and colony-stimulating activity in grey collie dogs. Blood. 1982 Jan;59(1):179–184. [PubMed] [Google Scholar]
- Hammond W. P., Dale D. C. Lithium therapy of canine cyclic hematopoiesis. Blood. 1980 Jan;55(1):26–28. [PubMed] [Google Scholar]
- Hammond W. P., Engelking E. R., Dale D. C. Cyclic hematopoiesis. Effects of endotoxin on colony-forming cells and colony-stimulating activity in grey collie dogs. J Clin Invest. 1979 Apr;63(4):785–792. doi: 10.1172/JCI109363. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hartwick R. A., Brown P. R. Evaluation of microparticle chemically bonded reversed-phase packings in the high-pressure liquid chromatographic analysis of nucleosides and their bases. J Chromatogr. 1976 Nov 3;126:679–691. doi: 10.1016/s0021-9673(01)84111-x. [DOI] [PubMed] [Google Scholar]
- Hartwick R. A., Brown P. R. The performance of microparticle chemically-bonded anion-exchange resins in the analysis of nucleotides. J Chromatogr. 1975 Oct 29;112:650–662. doi: 10.1016/s0021-9673(00)99994-1. [DOI] [PubMed] [Google Scholar]
- Jones J. B., Yang T. J., Dale J. B., Lange R. D. Canine cyclic haematopoiesis: marrow transplantation between littermates. Br J Haematol. 1975 Jun;30(2):215–223. doi: 10.1111/j.1365-2141.1975.tb00535.x. [DOI] [PubMed] [Google Scholar]
- Lange R. D., Jones J. B., Chambers C., Quirin Y., Sparks J. C. Erythropoiesis and erythrocytic survival in dogs with cyclic hematopoiesis. Am J Vet Res. 1976 Mar;37(3):331–334. [PubMed] [Google Scholar]
- Lund J. E., Padgett G. A., Ott R. L. Cyclic neutropenia in grey collie dogs. Blood. 1967 Apr;29(4):452–461. [PubMed] [Google Scholar]
- Martin D. W., Jr, Gelfand E. W. Biochemistry of diseases of immunodevelopment. Annu Rev Biochem. 1981;50:845–877. doi: 10.1146/annurev.bi.50.070181.004213. [DOI] [PubMed] [Google Scholar]
- Osborne W. R. Human red cell purine nucleoside phosphorylase. Purification by biospecific affinity chromatography and physical properties. J Biol Chem. 1980 Aug 10;255(15):7089–7092. [PubMed] [Google Scholar]
- Osborne W. R., Spencer N. Partial purification and properties of the common inherited forms of adenosine deaminase from human erythrocytes. Biochem J. 1973 May;133(1):117–123. doi: 10.1042/bj1330117. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Parks R. E., Jr, Brown P. R., Cheng Y. C., Agarwal K. C., Kong C. M., Agarwal R. P., Parks C. C. Purine metabolism in primitive erythrocytes. Comp Biochem Physiol B. 1973 Jun 15;45(2):355–364. doi: 10.1016/0305-0491(73)90070-9. [DOI] [PubMed] [Google Scholar]
- Patt H. M., Lund J. E., Maloney M. A. Cyclic hematopoiesis in grey collie dogs: a stem-cell problem. Blood. 1973 Dec;42(6):873–884. [PubMed] [Google Scholar]
- Schmalstieg F. C., Nelson J. A., Mills G. C., Monahan T. M., Goldman A. S., Goldblum R. M. Increased purine nucleotides in adenosine deaminase-deficient lymphocytes. J Pediatr. 1977 Jul;91(1):48–51. doi: 10.1016/s0022-3476(77)80442-3. [DOI] [PubMed] [Google Scholar]
- Sullivan J. L., Osborne W. R., Wedgewood R. J. Adenosine deaminase activity in lymphocytes. Br J Haematol. 1977 Sep;37(1):157–158. [PubMed] [Google Scholar]
- TRUBOWITZ S., FELDMAN D., MORGENSTERN S. W., HUNT V. M. The isolation, purification and some properties of the alkaline phosphatase of human leucocytes. Biochem J. 1961 Aug;80:369–374. doi: 10.1042/bj0800369. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Thelander L., Reichard P. Reduction of ribonucleotides. Annu Rev Biochem. 1979;48:133–158. doi: 10.1146/annurev.bi.48.070179.001025. [DOI] [PubMed] [Google Scholar]
- Tung R., Silber R., Quagliata F., Conklyn M., Gottesman J., Hirschhorn R. Adenosine deaminase activity in chronic lymphocytic leukemia. Relationship to B- and T-cell subpopulations. J Clin Invest. 1976 Mar;57(3):756–761. doi: 10.1172/JCI108334. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Weiden P. L., Robinett B., Graham T. C., Adamson J., Storb R. Canine cyclic neutropenia. A stem cell defect. J Clin Invest. 1974 Mar;53(3):950–953. doi: 10.1172/JCI107636. [DOI] [PMC free article] [PubMed] [Google Scholar]