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Proliferation-linked Regulation of Type II IMP Dehydrogenase Gene in Human Normal Lymphocytes and HL-60 Leukemic Cells¹

Laboratory for Experimental Oncology [M. N., Y. N., G. W.] and Walther Oncology Center [M. N.], Indiana University School of Medicine, Indianapolis, Indiana 46202-5200

Human IMP dehydrogenase (IMPDH; EC 1.1.1.205) was recently found to consist of two molecular species (types I and II) with high expression of type II isozyme in leukemic cells. Here we report that the low level of type II mRNA in normal lymphocytes was up-regulated by phytohemagglutinin stimulation (3.2-fold) and Epstein-Barr viral transformation (5.7-fold). The type II mRNA expression in quiescent HL-60 cells was also elevated 2.8-fold by serum stimulation. Conversely the enhanced level of type II IMPDH mRNA in HL-60 cells was down-regulated to less than 5% along with differentiation induced by retinoic acid (1 µM), phorbol-12-myristate-13-acetate (33 nM), or dimethyl sulfoxide (1.25%) independent of end-stage phenotype. By contrast, type I IMPDH mRNA was expressed constitutively in the various states of proliferation and differentiation. The type II IMPDH stringently linked with cell proliferation should be a crucial target for antileukemic and immunosuppressive chemotherapy.

¹ This work was supported in part by USPHS Outstanding Investigator Grant CA-42510 and American Cancer Society Grant RD-288 awarded to G. W., and by American Cancer Society Institutional Grant IN-161-D awarded to M. N.

² To whom requests for reprints should be addressed.

Received 8/16/91. Accepted 11/ 1/91.

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