12-hydroxy-5-8-10-14-eicosatetraenoic-acid and Blast-Crisis

Several reports have demonstrated an important role of leukotriene B(4) (LTB(4)) in the immune system. We investigated whether leukemic blasts from acute myeloid leukemic (AML) and acute lymphoid leukemic (ALL) patients produced LTB(4), 12- and 15-hydroxyeicosatetraenoic acids (12-HETE and 15-HETE) and whether these compounds affected blast proliferation and apoptosis. Leukemic blasts from AML M(0-2) and ALL patients expressed 5-LOX, 12-LOX and 15-LOX transcripts. Quantitative polymerase chain reaction indicated that 5-LOX transcripts were far more abundant than 12-LOX and 15-LOX ones. Leukemic blasts expressed 5-LOX activating protein (FLAP) transcripts and produced LTB(4) in response to calcium ionophore. In contrast no 15-HETE production was found. Calcium ionophore-stimulated leukemic blasts produced 12-HETE but also released thromboxane A(2) suggesting that contaminating platelets accounted for the release of these compounds. No significant effect of LTB(4), 12-HETE or 15-HETE could be documented on leukemic blast growth and on their apoptose rate. Results of the present study indicate that immature form of leukemic blasts produce LTB(4). However, the three major lipoxygenase metabolites of arachidonic acid; i.e., LTB(4), 12-HETE or 15-HETE, had no evident effect on their growth and apoptosis. We may speculate that LTB(4)-derived blast cells might initiate, augment or prolong tissue inflammation and damages by affecting the marrow and blood cytokine network.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Apoptosis; Arachidonate 12-Lipoxygenase; Arachidonate 15-Lipoxygenase; Arachidonate 5-Lipoxygenase; Arachidonic Acid; Blast Crisis; Calcium; Cell Proliferation; Humans; Hydroxyeicosatetraenoic Acids; Ionophores; Leukemia, Myeloid, Acute; Leukotriene B4; Polymerase Chain Reaction; Precursor Cell Lymphoblastic Leukemia-Lymphoma; RNA, Messenger; Thromboxane A2

The capacity to convert exogenous leukotriene A4 to lipoxins (LXs) was investigated in platelet suspensions from patients with myeloproliferative disorders (MPD) (n = 22) and healthy control subjects (n = 14). Platelets isolated from the controls produced mainly LXA4, but also 6(S)-LXA4 and the all-trans isomers of lipoxins A4 and B4, as determined by high-performance liquid chromatography and computerized UV spectroscopy. In comparison to control levels, the mean LX synthesis was significantly lower in platelets from the MPD patients (438.7 +/- 62.8 and 157.4 +/- 31.2 pmol LXA4 per 10(9) platelets, respectively; mean +/- SEM; P = .0001). Platelets from six of the patients showed a particularly low capacity to produce LXs, resulting in LX levels below the detection limit or less than 7% of mean control levels. Notably, all these patients were in blastic crisis of chronic myelogenous leukemia (CML). This severely deficient LX production was paralleled by a dramatically attenuated conversion of arachidonic acid to 12-HETE (12-hydroxyheptadecatrienoic acid), a product formed via the prostaglandin endoperoxide synthase pathway, was normal. In addition, longitudinal studies of CML patients showed that blastic metamorphosis was associated with a markedly reduced capability to synthesize LXs, while this capacity improved after retransformation into a second chronic phase. The results reveal deficient LX synthesis as a novel platelet dysfunction in MPD, particularly in blastic crisis of CML in which an essentially abolished 12-lipoxygenase activity may be a general phenomenon.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Blast Crisis; Blood Platelets; Fatty Acids, Unsaturated; Humans; Hydroxyeicosatetraenoic Acids; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukotriene A4; Leukotrienes; Lipoxins; Myeloproliferative Disorders; SRS-A