Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

L-696,229 is a potent and specific inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase and is currently undergoing clinical evaluation. In vivo metabolism in rats was investigated using an intravenous bolus dose of 5 mg/kg [3H]L-696,229. The amount of radioactivity eliminated in bile and urine over a period of 6 hr was 60 and 22%, respectively. Radiochromatographic analysis of the bile and urine showed that L-696,229 was metabolized rapidly and completely to several common metabolites. Sequential oxidation at the alpha-position of the 5-ethyl group to an acetyl moiety, aromatic hydroxylation of the benzoxazole group (position C4', C6', or C7'), and subsequent sulfate conjugation were the major metabolic pathways as determined by the application of enzymatic hydrolysis, FAB-MS, and 1H- and 13C-NMR spectroscopies. The in vitro metabolism of this 2-pyridinone derivative with rat liver slices resulted primarily in hydroxylation at the 6-methyl and 5-ethyl groups. The 6-hydroxymethyl- and 5-alpha-hydroxyethyl analogs were also inhibitors of HIV-1 reverse transcriptase.
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PMID:Metabolism of a new HIV-1 reverse transcriptase inhibitor, 3-[2-(benzoxazol-2-yl)ethyl]-5-ethyl-6-methylpyridin-2(1H)-one (L-696,229), in rat and liver slices. 128 69

We report two cases of acute lymphoblastic leukemia (ALL) with a late-appearing Philadelphia chromosome (Ph1), confirmed by the expression of BCR-ABL mRNA, using the reverse transcriptase/polymerase chain reaction (RT/PCR) technique. The first patient was a 10-year-old boy with precursor B cell type ALL-L1 (FAB classification). At diagnosis, no metaphase cells were found by chromosome analysis and BCR-ABL mRNA was not observed. At the beginning of relapse, which occurred after 7 months of complete remission, a normal karyotype was observed. At the terminal stage, leukemic cells with Ph1 and BCR-ABL mRNA for the P190 variety were observed. The second patient was a 12-year-old boy with immature T cell type ALL-L1. The metaphase cells showed a 9p- chromosome at diagnosis and Ph1 appeared in addition to 9p- at relapse. Hybrid mRNA for the P210 variety was detected only when Ph1 had developed. The blast cells with Ph1 were derived from the original leukemic clone through clonal evolution, since the same clonal rearrangements of IGH or TCRB were detected in leukemic cells obtained both at diagnosis and relapse in both patients. Thus, in both cases, Ph1 was detected only in the course of ALL along with expression of BCR-ABL mRNA. This observation also confirmed that, as in de novo Ph1-positive ALL, both the P190 and P210 varieties of BCR-ABL mRNA are observed in ALL with late-appearing Ph1.
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PMID:A late-appearing Philadelphia chromosome in acute lymphoblastic leukemia confirmed by expression of BCR-ABL mRNA. 756 11

We present a 15-year-old woman with acute myelomonocytic leukemia without marrow eosinophilia, M4 in the FAB classification. She was admitted to our hospital with nausea and headaches. Upon admission, the leukocyte count was 284,000/microliters with 95% leukemic cells. The bone marrow aspirate was hypercellular with 74.8% blasts and 0.2% eosinophils. Leukemic cells were positive for myeloperoxidase and esterase staining. Initially, the karyotype of the bone marrow cells on admission was considered to be normal. However, the PEBP2 beta/MYH11 fusion transcript was detected in the bone marrow mononuclear cells by using the reverse transcriptase-polymerase chain reaction (RT-PCR). Reevaluation of karyotypes showed a t(16;16) (p13;q22) in the bone marrow cells. After achieving complete remission, she was treated with low-dose etoposide. Chromosome analysis showed a normal karyotype and no amplified chimeric transcripts were observed. This case indicates that the molecular analysis of PEBP2 beta and MYH11 genes is a useful tool to detect inv (16) and t(16;16) which were often difficult to find, and that leukemic cells from some cases of M4 without marrow eosinophilia have these chromosome abnormalities.
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PMID:[Detection of PEBP2 beta/MYH11 fusion mRNA in acute myelomonocytic leukemia without marrow eosinophilia]. 877 82

Nerve growth factor (NGF) is of major importance for the survival, development and maintenance of peripheral sympathetic and central neuronal tissue. Most of the cellular effects are mediated by binding to their high-affinity receptor c-TRK, a transmembrane receptor tyrosine kinase. C-TRK protein has been detected in neuronal tissue and also in mast cells, monocytes and some haemopoletic progenitor cells. Here we report c-TRK gene expression in myeloid leukaemic cell lines (HEL, K562 and KG-1) and for the first time in the primary leukaemic cells of 44% (n = 59) of patients with acute myelogenous leukaemia (AML). Moreover, in the human promyelocytic cell line HL-60, c-TRK expression was inducible by differentiation induction with tetradecanoyl-phorbol 13-acetate (TPA). In c-TRK gene-expressing cells the transmembrane receptor tyrosine kinase was detectable by Western blotting and by in vitro kinase assay. In the AML group, c-TRK expression was not correlated to the FAB-classified morphology or any other clinical parameter. In all cases tested we could not detect NGF mRNA by means of reverse transcriptase PCR, excluding an autocrine loop involving the TRK/NGF receptor-ligand system in leukaemogenesis. Our results show another example of possible communication between neuronal and haemopoietic tissue. However, we still lack positive evidence of a c-TRK function in haemopoiesis.
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PMID:Expression of the nerve growth factor receptor c-TRK in human myeloid leukaemia cells. 885 45

B lineage-derived malignant proliferation is a well recognized complication of HIV infection. Acute myeloid leukemias have been reported but no complete review of these cases has been performed. The Medline database was reviewed for the years 1980-1997. Eighteen cases of AML have been reported. When previously known, HIV infection was present for 40 months. In 7 patients HIV infection and AML were diagnosed simultaneously. According to the FAB classification, 5 cases were M2, 8 M4, 5 M5. Extramedullary localizations (skin, testis, spleen) were noticed in 10 patients. Non-treated patients had a survival of 2.7 weeks versus 9.8 months in patients treated with chemotherapy. Pathophysiologic studies were performed in 3 cases: reverse transcriptase activity and p24 antigen were noted in tumoral cultured cells in 1 case; absence of viral particules in culture in another one; absence of cloned DNA provirus integration in blasts cells in a third patient. Based on the observed high rate of M4/M5 (72%) versus 19-36% expected in a non HIV-infected population, we postulate that the association of AML and HIV is not coincidental. The monocytotropism of HIV, the chronic cytokines-mediated activation of monocyte/macrophages, the immunodeficiency may explain this association.
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PMID:[Acute myelocytic leukemia in immunodeficiency virus infection]. 1002 98

We report the cellular characteristics of cells from three patients with de novo acute myelocytic leukaemia (AML) with t(16;21)(p11;q22), two M4 and one M5a according to the FAB classification, and two permanent cell lines with t(16;21)(p11;q22), TSU1621MT and YNH-1. The FUS/ERG fusion mRNA was demonstrated in all cases by reverse transcriptase-polymerase chain reaction (RT-PCR). The immunophenotypes of the AML cells, and YNH-1 and TSU1621MT cell lines with t(16;21) were characterized as CD34+CD33+CD13+CD11b+CD18+CD56+ HLA-DR-/+. Cells from all samples strongly expressed c-kit, granulocyte colony-stimulating factor receptor (G-CSFR), c-fms (macrophage colony-stimulating factor receptor), interleukin-3 receptor alpha chain (IL-3Ralpha), and granulocyte macrophage colony-stimulating factor receptor alpha chain (GM-CSFRalpha), and these data corresponded well to the growth responsiveness to the cytokines. IL-2Ralpha expression was also found in all t(16;21) samples, but IL-2 did not act on the proliferation of the leukaemic cells in in vitro cultures. G-CSF distinctly promoted the proliferation of leukaemic cells of t(16;21) AML, but did not enhance the expression of MPO and neutrophil differentiation of these cells. Our findings indicate that AML cells with t(16;21) preserve stem cell properties such as CD34 and c-kit expression, and suggest that they have the potential to differentiate into a monocytic lineage. The relationship between the unique cellular characteristics (especially CD56 and IL-2Ralpha expression) and FUS/ERG protein remains undetermined.
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PMID:Myeloid differentiation antigen and cytokine receptor expression on acute myelocytic leukaemia cells with t(16;21)(p11;q22): frequent expression of CD56 and interleukin-2 receptor alpha chain. 1035 36

Receptor tyrosine kinases (RTK) play a significant role in the signal transduction of normal, and malignant hematopoietic cells. We have previously shown that Axl, a novel RTK, is mainly expressed in leukemias of myeloid origin, and that its expression may be associated with cells of monocytic origin. Since expression of certain RTKs in cancer may be associated with different biology and survival, we investigated whether the expression of Axl is associated with clinical characteristics and survival in acute myeloid leukemia (AML). RNA from 54 patients with AML treated in a cooperative group trial was analyzed in a retrospective and blinded manner using a semi-quantitative reverse transcriptase polymerase chain reaction-based assay with primers specific for the Axl gene. Axl expression was found in 19 out of the 54 cases (35%). Axl expression was not detected more frequently in patients of older age, specific FAB categories, or cases with extramedullary disease. However, there existed a correlation between Axl and bcl-2 expression levels. AML cells with high bcl-2 expression showed higher Axl expression (r = 0.32; P = 0.02), and furthermore, Axl transcript numbers were also higher in AML with high CD34 expression (n = 38, r = 0.42; P = 0.008). No significant difference between leukemias expressing and not expressing Axl was found with regard to complete remission rate. However, quantitative Axl expression was associated with worse progression-free and overall survival. Higher Axl levels had worse prognosis for progression-free (beta: 0.68, s.e.: 0.28, P = 0.015) and overall survival (beta: 0.61, s.e.: 0.31, P = 0.05) using multivariate Cox models adjusted for age, Auer rods and leukocyte counts. In conclusion, in this retrospective analysis, no difference with regard to clinical characteristics at diagnosis was found between AML patients whose leukemia cells show Axl expression vs patients whose cells are Axl negative. The association between Axl and bcl-2 and Axl and CD34 expression in de novo AML needs further investigation. Similarly, the negative impact of Axl levels on outcome should be confirmed in a larger cohort.
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PMID:Axl expression is associated with adverse prognosis and with expression of Bcl-2 and CD34 in de novo acute myeloid leukemia (AML): results from a multicenter trial of the Swiss Group for Clinical Cancer Research (SAKK). 1048 85

Angiogenesis plays a key role in solid tumor growth. The purpose of this work was to study angiogenesis in acute myeloid leukemia (AML). We stained bone marrow samples from 20 adult patients with untreated AML and 20 normal controls using endothelial cell markers (ULEX-E and von Willebrand factor [vWF]). The number of vessels per millimeter length of bone marrow core biopsy specimen was scored by light microscopy. Using ULEX-E staining, AML marrows had (average +/- SEM) 8.3 +/- 3.6 vessels/mm (range, 3.7-19.3), whereas normal marrows had 4.3 +/- 1.8 vessels/mm (range, 1.6-7.9). A similar difference was noted using vWF staining (8.6 +/- 3.0 vessels/mm vs 4. 9 +/- 2.2 vessels/mm in AML vs normal bone marrows, respectively). The differences between the numbers of vessels/mm in AML and normal marrows were highly significant (P <.0001 for both ULEX-E and vWF staining). When analyzed by FAB category, there was no difference in the average number of vessels/mm among the different subgroups of AML. Using reverse transcriptase polymerase chain reaction, we observed that the HL-60 and U937 human AML cell lines and 4 of 4 freshly isolated AML cells from untreated patients expressed mRNA for vascular endothelial growth factor (VEGF). Both cell lines as well as all fresh AML isolates tested expressed VEGF protein. Basic fibroblast growth factor was expressed only in HL-60 cells and in only 3 of 4 fresh AML samples. These observations suggest that angiogenesis may play a role in the pathogenesis of AML. Inhibition of angiogenesis could constitute a novel strategy for the treatment of AML. (Blood. 2000;95:309-313).
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PMID:Evidence of increased angiogenesis in patients with acute myeloid leukemia. 1118 59

MLF1 is a novel protein identified as the NPM-MLF1 chimeric protein produced by a t(3;5)(q25.1;q34) chromosomal translocation, which is associated with myelodysplastic syndrome (MDS), often prior to acute myeloid leukemia (AML), except for M3. The clinical features of t(3;5)-positive myeloid disorders suggest that this chimeric protein is involved in dysregulation of progenitor cells with the capability to differentiate into multiple lineages. So far, involvement of wild-type MLF1 in hematopoiesis or in leukemogenesis has not been fully investigated. In the present study, 65 patients with AML and 44 patients with MDS were tested for the expression of MLF1 using the quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) method. A significantly higher level of MLF1 expression (ratio of MLF1/beta-actin mRNA >0.4) was readily detected in seven of 65 patients with de novo AML, three of 12 with post-MDS AML and seven of 44 with MDS, but not in any patients with ALL (n = 18). According to the FAB classification, high levels of MLF1 were found in patients with relatively immature subtypes of AML (M1, M2, M6 and M7) and high risk MDS (RAEB and RAEB-T). These findings indicate that the pattern of MLF1 expression is identical to the clinical morphology appearing in the t(3;5)-positive myeloid disorders and is correlated to the MDS-associated AML and transformation phase of MDS in t(3;5)-negative myeloid disorders. A CD34+ population of normal bone marrow cells preferentially expressed MLF1 with obviously decreasing levels of expression during maturation. Therefore, MLF1 normally functions in multi-potent progenitor cells and its dysregulation may take part in leukemogenesis from MDS.
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PMID:Elevated MLF1 expression correlates with malignant progression from myelodysplastic syndrome. 1102 51

In a case of acute monocytic leukemia, M5a according to the FAB classification, with a 48,XY,+8,+22 karyotype, amplification of the CBFbeta/MYH11 fusion transcript type A was detected by reverse transcriptase-polymerase chain reaction (RT-PCR). Fluorescence in situ hybridization (FISH) using an appropriate panel of DNA probes showed that insertion of the 3'-MYH11 within the CBFbeta gene on chromosome 16q22 was the mechanism producing the same molecular rearrangement as in typical inv(16)(p13q22)/t(16;16)(p13;q22).
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PMID:Typical CBFbeta/MYH11 fusion due to insertion of the 3'-MYH11 gene into 16q22 in acute monocytic leukemia with normal chromosomes 16 and trisomies 8 and 22. 1115 Jun 5


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