INACTIVATION OF CALCIUM ION-REGULATING INOSITOL POLYPHOSPHATE 2ND-MESSENGERS IS IMPAIRED IN SUBPOPULATIONS OF HUMAN LEUKEMIA-CELLS

Inositol 1,4,5-triphosphate (IP3) and inositol 1,3,4,5-tetrakis-phosph ate (IP4) are calcium-regulating second messenger molecules generated following the binding of a wide range of hormones and growth factors t o their receptors. The actions of these messengers, which play importa nt roles in the regulation of cell proliferation as well as in other s ignaling pathways, are terminated by the action of a 5-phosphomonoeste rase (5-PME) enzyme. We have assayed this enzyme in normal and maligna nt hemopoietic cells. Extracts from normal bone marrow cells and perip heral blood mononuclear cells (PBMNC) degraded [H-3]IP3 at rates of 74 .5 (+/-3.4) and 84.5 (+/-7.9) pmol/min/mu g protein, respectively. PME activity in 10/13 (77%) acute lymphoblastic leukemia samples were sig nificantly below the normal range and the enzyme was completely undete ctable in three (23%) of these. Enzyme activity in 8/9 (89%) chronic l ymphocytic leukemia samples was below the normal range, being undetect able in three of these (33%). Nine of 24 (38%) acute myeloid leukemia samples contained low 5-PME levels, which was undetectable in one samp le. Reduced 5-PME activity was detected in 2/7 (28%) of chronic granul ocytic leukemia samples. The data here are consistent with the hypothe sis that a reduced rate of degradation of IP3 and IP4 in some leukemia cells may result in the aberrant operation of signaling pathways, pos sibly including those involved in the control of cell proliferation.