Impaired degradation of Ca(2+)-regulating second messengers in myeloid leukemia cells. Implications for the regulation of leukemia cell proliferation.

Inositol 1,4,5-trisphosphate and inositol 1,3,4,5-tetrakisphosphate are Ca(2+)-regulating second messenger molecules which are generated via the cleavage of inositol lipids. We have previously shown that these species are autonomously generated in HL60 myeloid leukemia cells and that they may play a role in signalling the continuous proliferation of this cell line. Here we show that the activity of the 5-phosphomonoesterase (5-PME) enzyme which cleaves and inactivates these second messengers was strikingly reduced in HL60 cells compared to normal granulocytes or macrophages. Induction of differentiation of HL60 cells along the monocyte/macrophage or granulocytic pathways did not result in a significant increase in 5-PME activity. The activity of this enzyme was also low in extracts of bone marrow mononuclear cells from four patients with myeloid leukemia. A lesion in the 5-PME pathway may therefore result in the conservation of Ca(2+)-regulating second messengers in the HL60 cell line and in some myeloid leukemia cells. It is plausible that this lesion may co-operate with the autonomous cleavage of inositol lipids in the signalling of leukemic cell proliferation.