This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yu, J. Articles by Yu, A. L. Search for Related Content PubMed PubMed Citation Articles by Yu, J. Articles by Yu, A. L.

Induction of Erythroid Differentiation in K562 Cells by Inhibitors of Inosine Monophosphate Dehydrogenase¹

Department of Molecular and Experimental Medicine, Research Institute of Scripps Clinic, La Jolla, California 92037 [J. Y., V. L.], and Department of Pediatrics, University of California at San Diego, La Jolla, California 92093 [T. P., J. D. C., A. L. Y.]

The effects of three inhibitors of inosine monophosphate (IMP) dehydrogenase on a human erythroleukemic cell line, K562, were studied. Following incubation with these inhibitors, K562 cells underwent differentiation and accumulated hemoglobins. The induction of hemoglobin accumulation was dose dependent; maximum induction was observed at 100, 25, and 3 µM, respectively, for ribavirin, tiazofurin, and mycophenolic acid. The induction was associated with reduction of intracellular GTP content and was blocked by adding guanosine within 24 h after adding inducer. The effective dose for half-maximum induction by ribavirin was 3 times less than that for 50% inhibition of K562 proliferation; however, for tiazofurin and mycophenolic acid, it closely approximated the concentrations which suppressed cellular proliferation. Ribavirin was sequestered preferentially inside the K562 cells, and the induction by ribavirin had a greater than 30-fold increase in hemoglobin. Studies with isoelectric focusing, globin chain analyses, and immunochemical assays indicated that both A and G were detected and that the hemoglobin produced in the ribavirin-treated cells consisted of approximately 60% fetal hemoglobin and its acetylated equivalents. The adult-type globin was found, while no ß globin chains were demonstrated. Thus, accumulation of fetal hemoglobin and production of globin chain in ribavirin-treated cells are different from the pattern of hemoglobins induced by hemin.

¹ This work was supported in part by grants from the NIH (DK 37039 and CA 40186). This is Publication 5408-BCR from the Research Institute of Scripps Clinic, La Jolla, Ca.

² To whom requests for reprints should be addressed at Department of Basic and Clinical Research, BCR3, Research Institute of Scripps Clinic, 10666 North Torrey Pines Road, La Jolla, CA 92037.

Received 6/13/88. Revised 11/ 4/88. Revised 4/17/89. Revised 7/ 7/89. Accepted 7/20/89.

This article has been cited by other articles:

				J. J. Gu, K. Gathy, L. Santiago, E. Chen, M. Huang, L. M. Graves, and B. S. Mitchell Induction of apoptosis in IL-3-dependent hematopoietic cell lines by guanine nucleotide depletion Blood, June 15, 2003; 101(12): 4958 - 4965. [Abstract] [Full Text] [PDF]

				B. J. Barnes, R. A. Izydore, A. E. Eakin, and I. H. Hall Induction of Tmolt4 Leukemia Cell Death by 3,3-Disubstituted-6,6-pentamethylene-1,5-diazabicyclo[3.1.0]hexane-2,4-diones: Specificity for Type II Inosine 5'-Monophosphate Dehydrogenase J. Pharmacol. Exp. Ther., August 1, 2001; 298(2): 790 - 796. [Abstract] [Full Text] [PDF]

				J. J. Gu, J. Spychala, and B. S. Mitchell Regulation of the Human Inosine Monophosphate Dehydrogenase Type I Gene. UTILIZATION OF ALTERNATIVE PROMOTERS J. Biol. Chem., February 14, 1997; 272(7): 4458 - 4466. [Abstract] [Full Text] [PDF]