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Selective Up-Regulation of Type II Inosine 5'-Monophosphate Dehydrogenase Messenger RNA Expression in Human Leukemias¹

Laboratory for Experimental Oncology [M. N., Y. N., Y. K., G. W.] and the Walther Oncology Center [M. N.], Division of Hematology and Oncology, Department of Medicine [R. H.], Indiana University School of Medicine, Indianapolis, Indiana 46202-5200, and the First Department of Internal Medicine, Kagawa Medical School, Kagawa 761-07, Japan [S. I.]

The discovery of isozymes (types I and II) of IMP dehydrogenase (IMPDH; EC 1.1.1.205), the rate-limiting enzyme of de novo GTP biosynthesis, has attracted attention as a possible novel approach to cancer diagnosis and selective tumor cell chemotherapy. To elucidate differences in expression and regulation of the two IMPDH isozymes, we examined the steady-state levels of these mRNAs in various types of leukemic cells from patients. Northern blot analysis revealed that type II IMPDH was more active transcriptionally (1.5- to 5.1-fold) in all the leukemic cells examined than in normal lymphocytes, whereas type I expression was similar. The increased expression of type II mRNA in leukemic cells was closely linked with the increase in total IMPDH activity (r = 0.92). When leukemic cells from a patient with chronic granulocytic leukemia in blast crisis were separated into blast-rich and mature leukocyte-rich fractions, the expression of type II mRNA correlated positively with the population of immature leukemic cells, whereas type I expression was unchanged. Treatment of leukemic blasts with 12-O-tetradecanoyl-phorbol-13-acetate for 5 days resulted in a 90% decrease in the expression of type II mRNA with macrophage-like differentiation, while the expression of type I mRNA was relatively stable. These observations suggest that expression of type II IMPDH is stringently linked with immature characteristics of leukemic cells; thus, it should be a selective target for antileukemic chemotherapy.

¹ This work was supported in part by USPHS Outstanding Investigator Grant CA-42510, 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, at Laboratory for Experimental Oncology, Indiana University School of Medicine, RR 337, 702 Barnhill Drive, Indianapolis, IN 46202-5200.

Received 3/26/91. Accepted 5/15/91.

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