NOVEL ENZYMATIC ABNORMALITIES IN AML AND CML IN BLAST CRISIS - ELEVATED LEUKOCYTE LEUKOTRIENE C-4 SYNTHASE ACTIVITY PARALLELED BY DEFICIENTLEUKOTRIENE BIOSYNTHESIS FROM ENDOGENOUS SUBSTRATE

Leukotrienes (LT) are inflammatory mediators which can also exert regu latory effects on human myelopoiesis, We have studied the LT-producing capacity of freshly isolated leucocyte suspensions (containing blast cells in variable proportions) from 41 patients with acute myeloid leu kaemia (AML) or chronic myeloid leukaemia (CML) in blast crisis (CMLbc ) at diagnosis or relapse/resistant disease. Leucocyte suspensions fro m 19/29 AML patients (66%), and 2/12-CMLbc patients (17%; P=0.012) dem onstrated deficient capacity to synthesize LT from endogenous substrat e after ionophore A23187 stimulation. Thus, these cells produced <8pmo l LTB4+LTC4/10(6) cells (<20% of mean LT formation in leucocyte suspen sions from 18 healthy subjects). Addition of exogenous arachidonic aci d did not normalize the LT synthesis in poor-producing cell suspension s. Purified, morphologically mature granulocytes from two AML patients also failed to produce normal amounts of LT. In leucocyte suspensions from the remaining 20 AML/CMLbc patients A23187 provoked LT biosynthe sis, with markedly increased production of LTC4, but decreased LTB4 fo rmation. Furthermore, elevated conversion of exogenous LTA(4) to LTC4 was noted in the patient samples, independent of their capacity to pro duce LT after A23187 stimulation. The percentage of blast cells in pat ient white blood cell differential counts correlated inversely with io nophore-induced LT synthesis, but positively with the conversion of ex ogenous LTA4 to LTC4. The results suggest elevated LTC4 synthase activ ity and suppressed 5-lipoxygenase activity as novel enzymatic features of myeloid leukaemia patients with immature phenotype.