Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Leukotrienes (LT) are inflammatory mediators which can also exert regulatory 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 leukaemia (AML) or chronic myeloid leukaemia (CML) in blast crisis (CMLbc) at diagnosis or relapse/resistant disease. Leucocyte suspensions from 19/29 AML patients (66%), and 2/12 CMLbc patients (17%; P = 0.012) demonstrated deficient capacity to synthesize LT from endogenous substrate after ionophore A23187 stimulation. Thus, these cells produced < 8 pmol LTB4+LTC4/10(6) cells (< 20% of mean LT formation in leucocyte suspensions from 18 healthy subjects). Addition of exogenous arachidonic acid did not normalize the LT synthesis in poor-producing cell suspensions. 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 biosynthesis, with markedly increased production of LTC4, but decreased LTB4 formation. Furthermore, elevated conversion of exogenous LTA4 to LTC4 was noted in the patient samples, independent of their capacity to produce LT after A23187 stimulation. The percentage of blast cells in patient white blood cell differential counts correlated inversely with ionophore-induced LT synthesis, but positively with the conversion of exogenous LTA4 to LTC4. The results suggest elevated LTC4 synthase activity and suppressed 5-lipoxygenase activity as novel enzymatic features of myeloid leukaemia patients with immature phenotype.
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PMID:Novel enzymatic abnormalities in AML and CML in blast crisis: elevated leucocyte leukotriene C4 synthase activity paralleled by deficient leukotriene biosynthesis from endogenous substrate. 967 47

Chronic myeloid leukemia (CML) is a hematopoietic stem cell disease, the hallmark of which is the Bcr-Abl protein tyrosine kinase (PTK). Without intervention the disease progresses from a benign chronic phase to a rapidly fatal blast crisis. To identify the molecular mechanisms underlying disease progression we used two-dimensional gel electrophoresis on a model we have previously described using the expression of a conditional mutant of Bcr-Abl PTK in a multipotent stem cell line, FDCP-Mix. Long term exposure of FDCP-Mix cells to Bcr-Abl mimics disease progression in CML. Four major differences were observed as a consequence of long term exposure to the Bcr-Abl PTK compared with cells exposed short term. The proteins were identified using matrix-assisted laser desorption ionization-time of flight mass spectrometry-generated peptide mass fingerprint data and liquid chromatography-tandem mass spectrometry-generated sequence information. Leukotriene A4 hydrolase, an enzyme known to be deregulated in CML, was found to be up-regulated. Annexin VI, vacuolar ATP synthase catalytic subunit A, and mortalin were found to be down-regulated. Poly(A) PCR cDNA analysis showed there was no correlation between the protein expression changes and mRNA levels. Western blot analysis also indicated no change in the levels of mortalin or leukotriene A4 hydrolase, indicating that post-translational events may modify protein content of the specific spots. Leukotriene B4 levels (product of leukotriene A4 hydrolase) were, however, reduced in cells exposed long term to Bcr-Abl activity. This study demonstrates the potential of proteomic analysis to define novel effects of oncogenes.
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PMID:Changes in the proteome associated with the action of Bcr-Abl tyrosine kinase are not related to transcriptional regulation. 1248 63

ALOX5 is implicated in chronic myeloid leukemia development in mouse leukemic stem cells, but its importance in human chronic myeloid leukemia is unknown. Functional ALOX5 was assessed using an LTB4 ELISA and ALOX5, and LTB4R1 mRNA expression was determined via a TaqMan gene expression assay. LTB4R1 and 5-LOX protein levels were assessed by cell surface flow cytometry analysis. At diagnosis ALOX5 was below normal in both blood and CD34(+) stem cells in all patients. On treatment initiation, ALOX5 levels increased in all patients except those who were destined to progress subsequently to blast crisis. LTB4 levels were increased despite low ALOX5 expression, suggesting that the arachidonic acid pathway is functioning normally up to the point of LTB4 production. However, the LTB4 receptor (BLT1) protein in newly diagnosed patients was significantly lower than after a period of treatment (P<0.0001). The low level of LTB4R1 at diagnosis explains the downregulation of ALOX5. In the absence of LTB4R1, the arachidonic acid pathway intermediates (5-HEPTE and LTA4) negatively regulate ALOX5. ALOX5 regulation is aberrant in chronic myeloid leukemia patients and may not be important for the development of the disease. Our data suggest caution when extrapolating mouse model data into human chronic myeloid leukemia.
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PMID:Low leukotriene B4 receptor 1 leads to ALOX5 downregulation at diagnosis of chronic myeloid leukemia. 2519 60