Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1984 Sep;74(3):821–827. doi: 10.1172/JCI111498

Induction of terminal differentiation in human K562 erythroleukemia cells by arabinofuranosylcytosine.

C Luisi-DeLuca, T Mitchell, D Spriggs, D W Kufe
PMCID: PMC425236  PMID: 6590568

Abstract

We have previously demonstrated that continuous exposure of human HL-60 human promyelocytes to 1-beta-D-arabinofuranosylcytosine (ara-C) results in the induction of terminal differentiation to monocyte-like cells. The present study extends these findings by demonstrating that ara-C induces hemoglobin synthesis in human K562 erythroleukemia cells. This effect occurs maximally at an ara-C concentration (5 X 10(-7) M) that results in K562 cytostasis. In contrast to the reversible effects of hemin and hydroxyurea on globin synthesis in this cell line, we have found that the induction of K562 hemoglobin synthesis by ara-C is irreversible. An induction of K562 hemoglobin synthesis also occurs with aphidicolin, another inhibitor of S-phase DNA synthesis, but not with vinblastine, an inhibitor of mitosis. Finally, ara-C induction of a differentiated K562 phenotype is accompanied by the loss of self-renewal capacity, a finding consistent with terminal differentiation.

Full text

PDF
821

Images in this article

823Image
on p.823
824Image
on p.824

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Baccarani M., Zaccaria A., Bandini G., Cavazzini G., Fanin R., Tura S. Low dose arabinosyl cytosine for treatment of myelodysplastic syndromes and subacute myeloid leukemia. Leuk Res. 1983;7(4):539–545. doi: 10.1016/0145-2126(83)90048-6. [DOI] [PubMed] [Google Scholar]
  2. Bodner A. J., Ting R. C., Gallo R. C. Induction of differentiation of human promyelocytic leukemia cells (HL-60) by nucleosides and methotrexate. J Natl Cancer Inst. 1981 Nov;67(5):1025–1030. [PubMed] [Google Scholar]
  3. Brown P. C., Tlsty T. D., Schimke R. T. Enhancement of methotrexate resistance and dihydrofolate reductase gene amplification by treatment of mouse 3T6 cells with hydroxyurea. Mol Cell Biol. 1983 Jun;3(6):1097–1107. doi: 10.1128/mcb.3.6.1097. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Castaigne S., Daniel M. T., Tilly H., Herait P., Degos L. Does treatment with ARA-C in low dosage cause differentiation of leukemic cells? Blood. 1983 Jul;62(1):85–86. [PubMed] [Google Scholar]
  5. Charnay P., Maniatis T. Transcriptional regulation of globin gene expression in the human erythroid cell line K562. Science. 1983 Jun 17;220(4603):1281–1283. doi: 10.1126/science.6574602. [DOI] [PubMed] [Google Scholar]
  6. Dean A., Erard F., Schneider A. P., Schechter A. N. Induction of hemoglobin accumulation in human K562 cells by hemin is reversible. Science. 1981 Apr 24;212(4493):459–461. doi: 10.1126/science.6163216. [DOI] [PubMed] [Google Scholar]
  7. Dean A., Ley T. J., Humphries R. K., Fordis M., Schechter A. N. Inducible transcription of five globin genes in K562 human leukemia cells. Proc Natl Acad Sci U S A. 1983 Sep;80(18):5515–5519. doi: 10.1073/pnas.80.18.5515. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Erard F., Dean A., Schechter A. N. Inhibitors of cell division reversibly modify hemoglobin concentration in human erythroleukemia K562 cells. Blood. 1981 Dec;58(6):1236–1239. [PubMed] [Google Scholar]
  9. Fram R. J., Kufe D. W. DNA strand breaks caused by inhibitors of DNA synthesis: 1-beta-D-arabinofuranosylcytosine and aphidicolin. Cancer Res. 1982 Oct;42(10):4050–4053. [PubMed] [Google Scholar]
  10. Frei E., 3rd, Bickers J. N., Hewlett J. S., Lane M., Leary W. V., Talley R. W. Dose schedule and antitumor studies of arabinosyl cytosine (NSC 63878). Cancer Res. 1969 Jul;29(7):1325–1332. [PubMed] [Google Scholar]
  11. Griffin J., Munroe D., Major P., Kufe D. Induction of differentiation of human myeloid leukemia cells by inhibitors of DNA synthesis. Exp Hematol. 1982 Oct;10(9):774–781. [PubMed] [Google Scholar]
  12. Huberman J. A. New views of the biochemistry of eucaryotic DNA replication revealed by aphidicolin, an unusual inhibitor of DNA polymerase alpha. Cell. 1981 Mar;23(3):647–648. doi: 10.1016/0092-8674(81)90426-8. [DOI] [PubMed] [Google Scholar]
  13. Kovach J. S., Marks P. A., Russell E. S., Epler H. Erythroid cell development in fetal mice: ultrastructural characteristics and hemoglobin synthesis. J Mol Biol. 1967 Apr 14;25(1):131–142. doi: 10.1016/0022-2836(67)90284-7. [DOI] [PubMed] [Google Scholar]
  14. Kufe D. W., Major P. P., Egan E. M., Beardsley G. P. Correlation of cytotoxicity with incorporation of ara-C into DNA. J Biol Chem. 1980 Oct 10;255(19):8997–8900. [PubMed] [Google Scholar]
  15. Kufe D., Spriggs D., Egan E. M., Munroe D. Relationships among Ara-CTP pools, formation of (Ara-C)DNA, and cytotoxicity of human leukemic cells. Blood. 1984 Jul;64(1):54–58. [PubMed] [Google Scholar]
  16. Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. doi: 10.1038/227680a0. [DOI] [PubMed] [Google Scholar]
  17. Lotem J., Sachs L. Potential pre-screening for therapeutic agents that induce differentiation in human myeloid leukemia cells. Int J Cancer. 1980 May 15;25(5):561–564. doi: 10.1002/ijc.2910250503. [DOI] [PubMed] [Google Scholar]
  18. Lozzio B. B., Lozzio C. B. Properties and usefulness of the original K-562 human myelogenous leukemia cell line. Leuk Res. 1979;3(6):363–370. doi: 10.1016/0145-2126(79)90033-x. [DOI] [PubMed] [Google Scholar]
  19. Major P. P., Egan E. M., Beardsley G. P., Minden M. D., Kufe D. W. Lethality of human myeloblasts correlates with the incorporation of arabinofuranosylcytosine into DNA. Proc Natl Acad Sci U S A. 1981 May;78(5):3235–3239. doi: 10.1073/pnas.78.5.3235. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Major P. P., Egan E. M., Herrick D. J., Kufe D. W. Effect of ARA-C incorporation on deoxyribonucleic acid synthesis in cells. Biochem Pharmacol. 1982 Sep 15;31(18):2937–2940. doi: 10.1016/0006-2952(82)90266-0. [DOI] [PubMed] [Google Scholar]
  21. Manservigi R., Spear P. G., Buchan A. Cell fusion induced by herpes simplex virus is promoted and suppressed by different viral glycoproteins. Proc Natl Acad Sci U S A. 1977 Sep;74(9):3913–3917. doi: 10.1073/pnas.74.9.3913. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. McCulloch E. A., Buick R. N., Curtis J. E., Messner H. A., Senn J. S. The heritable nature of clonal characteristics in acute myeloblastic leukemia. Blood. 1981 Jul;58(1):105–109. [PubMed] [Google Scholar]
  23. Orkin S. H., Harosi F. I., Leder P. Differentiation in erythroleukemic cells and their somatic hybrids. Proc Natl Acad Sci U S A. 1975 Jan;72(1):98–102. doi: 10.1073/pnas.72.1.98. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Rutherford T. R., Clegg J. B., Weatherall D. J. K562 human leukaemic cells synthesise embryonic haemoglobin in response to haemin. Nature. 1979 Jul 12;280(5718):164–165. doi: 10.1038/280164a0. [DOI] [PubMed] [Google Scholar]
  25. Rutherford T., Clegg J. B., Higgs D. R., Jones R. W., Thompson J., Weatherall D. J. Embryonic erythroid differentiation in the human leukemic cell line K562. Proc Natl Acad Sci U S A. 1981 Jan;78(1):348–352. doi: 10.1073/pnas.78.1.348. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Wisch J. S., Griffin J. D., Kufe D. W. Response of preleukemic syndromes to continuous infusion of low-dose cytarabine. N Engl J Med. 1983 Dec 29;309(26):1599–1602. doi: 10.1056/NEJM198312293092602. [DOI] [PubMed] [Google Scholar]
  27. Woodcock D. M., Adams J. K., Cooper I. A. Relationship between aberrant DNA replication and loss of cell viability in Chinese hamster ovary CHO-K1 cells. Cancer Res. 1982 Nov;42(11):4744–4752. [PubMed] [Google Scholar]
  28. Woodcock D. M., Cooper I. A. Evidence for double replication of chromosomal DNA segments as a general consequence of DNA replication inhibition. Cancer Res. 1981 Jun;41(6):2483–2490. [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES