P210 Bcr-Abl confers overexpression of inosine monophosphate dehydrogenase: An intrinsic pathway to drug resistance mediated by oncogene

Kamran Gharehbaghi, Gem S. Burgess, Frank R. Collart, Sara Litz-Jackson, Eliezer Huberman, Hiremagular N. Jayaram, H. Scott Boswell

Research output: Contribution to journalReview articlepeer-review

11 Scopus citations

Abstract

The p210 bcr-abl fusion protein tyrosine kinase oncogene has been implicated in the pathogenesis of chronic granulocytic leukemia (CGL). Specific intracellular functions performed by p210 bcr-abl have recently been delineated. We considered the possibility that p210 bcr-abl may also regulate the abundance of inosine 5'-monophosphate dehydrogenase (IMPDH) which is a rate-limiting enzyme for de novo guanylate synthesis. We performed studies of the inhibition of IMPDH by tiazofurin, which acts as a competitive inhibitor through its active species that mimics nicotinamide adenine dinucleotide (NAD), i.e. thiazole-4-carboxamide adenine dinucleotide (TAD). The mean inhibitory concentration (IC50 of tiazofurin for cellular proliferation inhibition was 2.3-2.8-fold greater in cells expressing p210 bcr-abl than in their corresponding parent cells proliferating under the influence of growth factors or in growth factor-independent derivative cells not expressing detectable p210 bcr-abl. IMPDH activity was 1.5-2.3-fold greater within cells expressing p210 bcr-abl than in their parent cells. This increase in enzyme activity was a result of 2-fold increased IMPDH protein as determined by immunoblotting. In addition, an increase in the K(m) value for NAD utilization by IMPDH was observed in p210 bcr-abl transformed cells, but this increase was within the range of resident NAD concentrations observed in the cells. Increased IMPDH protein in p210 bcr-abl transformed cells was traced to an increased level of IMP dehydrogenase II messenger RNA. Thus, regulation of IMPDH gene expression is mediated at least in part by the bcr-abl gene product and may therefore be indicative of a specific mechanism of intrinsic resistance to tiazofurin.

Original languageEnglish (US)
Pages (from-to)1257-1263
Number of pages7
JournalLeukemia
Volume8
Issue number8
StatePublished - Aug 1994

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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