Selective up-regulation of type II inosine 5'-monophosphate dehydrogenase messenger RNA expression in human leukemias.
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.
Nagai
M
M
Department of Medicine, Indiana University School of Medicine, Indianapolis 46202-5200.
Natsumeda
Y
Y
Konno
Y
Y
Hoffman
R
R
Irino
S
S
Weber
G
G
D002454:Cell Differentiation / Q000502:physiology; D004247:DNA / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D015973:Gene Expression Regulation, Leukemic / Q000502:physiology; D006413:Hematopoietic System / Q000166:cytology / Q000201:enzymology; D006801:Humans; D007168:IMP Dehydrogenase / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D007938:Leukemia / Q000201:enzymology* / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000502:physiology*
D007527:Isoenzymes; D012333:RNA, Messenger; D004247:DNA; D007168:IMP Dehydrogenase