Inverse relationship between myeloid maturation and leukotriene C4 synthase expression in normal and leukemic myelopoiesis -: consistent overexpression of the enzyme in myeloid cells from patients with chronic myeloid leukemia

Objective. Leukotriene (LT) C-4 synthase (LTC4S) is the key enzyme in the biosynthesis of LTC4, which has been reported to stimulate the growth of human myeloid progenitor cells and is specifically overproduced in chronic myeloid leukemia (CML). The aim of this study was to clarify the expression of LTC4S during normal and leukemic myelopoiesis and to investigate the correlation between abnormal LTC4S expression in CML myeloid cells and the activity of the disease-specific tyrosine kinase p210 BCR-ABL. Materials and Methods. Immature and mature myeloid cell subpopulations were isolated with magnetic cell sorting from healthy volunteer bone marrow (n = 11) and CML patient peripheral blood (n = 8), respectively. The cells were subjected to analysis of LTC4S protein expression and activity. Expression of LTC4S was investigated in CD16(+) neutrophils from CML patients before and after 1 month of medication with imatinib mesylate (STI571), which is a specific inhibitor of p210 BCR-ABL. Results. Among normal cells, the highest enzyme activity was observed in the most immature, CD34(+) progenitor cell-enriched and CD15(+) myelocyte-enriched fractions. Subsequently, LTC4S activity decreased with increasing maturity, with only negligible amounts of LTC4 produced in CD16(+) neutrophils. LTC4S was expressed at the protein level in the immature myeloid cell fractions but not in CD16(+) cells. In CML cells, LTC4S activity and expression were consistently elevated. Thus, the CML CD34(+) and CD15(+) cell fractions, as well as the CD11b(+) myelocyte/metamyelocyte-enriched fractions, produced 6 to 10 times as much LTC4 as the corresponding normal cells. Again, enzyme expression was highest in the most immature cells, although evident LTC4S expression and activity remained in CML CD16(+) neutrophils. Interestingly, treatment of five CML patients with imatinib mesylate down-regulated the abnormal neutrophil LTC4S expression and activity. Conclusions. Expression of LTC4S in immature myelopoid cells is in line with a role for this enzyme in myelopoiesis. In addition, consistent overexpression of LTC4S in CML and the correlation to p210 BCR-ABL activity suggests that LTC4S may be involved in leukemic pathogenesis. (C) 2003 International Society for Experimental Hematology.