Induction of cell differentiation by IMPDH antisense oligomer in HL-60 and K562 human leukemia cell lines.

Abstract

Inosine-5’-monophosphate dehydrogenase (IMPDH, EC 1.1.1.205) is the enzyme that catalyzes the formation of xanthosine-5’-monophosphate from inosine-5’-monophosphate (IMP). In the purine de novo synthetic pathway, IMPDH is positioned at the branch point in the synthesis of adenine and guanine nucleotides and is thus the rate-limiting enzyme in the de novo synthesis of guanine nucleotides. Alterations in the activity of IMPDH and the levels of guanine nucleotides have been implicated in the regulation of cell growth and differentiation[1]. The addition of IMPDH inhibitors, such as mycophenolic acid and tiazofurin, to cultures induces terminal differentiation in a variety of human leukemia cells, including K562 erythroid leukemia cells, and HL-60 myeloid leukemia cells as well as human breast cancer cells and melanoma cells[2–4]. To verify the role of this enzyme in controlling differentiation, we determined the ability of specific IMPDH antisense oligomers to induce maturation in the K562 and HL-60 human leukemia cell lines. From these experiments, we concluded that a specific reduction in IMPDH results in inhibition of cell replication and induction of terminal differentiation in the two human leukemia cell lines.