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)

Eight cases with Ph1 positive acute leukemia (7 of acute lymphocytic leukemia: ALL, and one of acute myelocytic leukemia: AML) were studied molecular biologically to identify location of breakpoints on BCR gene in each patient. Six of the 8 patients (5 of ALL and 1 of AML) had rearrangements at bcr (M-BCR) region. Their locations of the breakpoint in M-BCR were similar to those of 59 chronic myelocytic leukemia patients. One of the remaining two patients had gene rearrangements at m-BCR-1 region in BCR intron 1, and the last patient did not have gene rearrangements at any site of m-BCR-1 and IgL C lambda region. Two cases had gene deletion at either 3' or 5' side of the bcr. A patient with bcr rearrangement was also analyzed by PCR method with reverse transcriptase (RT-PCR) and had simultaneous expressions of bcr3-abl and bcr2-abl chimeric mRNAs. These results indicate that Ph1 positive acute leukemia have heterogeneous characteristics in terms of the molecular biology. The molecular analysis will help for classifying the leukemic types and for elucidating the pathogenesis in Ph1 positive acute leukemia.
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PMID:[Analysis of breakpoints on BCR gene in acute leukemia patients with Ph1 chromosome]. 154 9

Transformation of hematopoietic cells by the p210bcr/abl tyrosine kinase appears to require the expression of a functional MYC protein, suggesting that simultaneous targeting of BCR-ABL and c-myc might be a rational strategy for attempting treatment of Phil-adelphia leukemia. To test this hypothesis, severe combined immunodeficiency mice injected with Philadelphia leukemic cells were treated systemically with equal doses of bcr-abl or c-myc antisense oligodeoxynucleotides (ODNs) or with both ODNs in combination. Compared with the mice treated with individual agents, the disease process was much slower in the group treated with both ODNs, as revealed by flow cytometry, clonogenic assay, and reverse transcriptase-polymerase chain reaction analysis to detect leukemic cells in mouse tissue cell suspensions, and by enumeration of liver metastases. The retardation of the disease process was positively correlated with a markedly increased survival of leukemic mice treated with both ODNs. These data demonstrate the therapeutic potential of targeting multiple cooperating oncogenes.
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PMID:Leukemia treatment in severe combined immunodeficiency mice by antisense oligodeoxynucleotides targeting cooperating oncogenes. 750 9

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

The BCR/ABL oncogenic tyrosine kinase is responsible for initiating and maintaining the leukemic phenotype of Philadelphia chromosome (Ph1)-positive cells. Phosphatidylinositol-3 (PI-3) kinase is known to interact with and be activated by receptor and nonreceptor tyrosine kinases. We investigated whether PI-3 kinase associates with and/or is regulated by BCR/ABL, whether this interaction is functionally significant for Ph1 cell proliferation, and, if so, whether inhibition of PI-3 kinase activity can be exploited to eliminate Ph1-positive cells from bone marrow. We show that the p85 alpha subunit of PI-3 kinase associates with BCR/ABL and that transient expression of BCR/ABL in fibroblasts and down-regulation of BCR/ABL expression using antisense oligodeoxynucleotides (ODNs) in Ph1 cells activates and inhibits, respectively, PI-3 kinase enzymatic activity. The use of specific ODNs or antisense constructs to downregulate p85 alpha expression showed a requirement for p85 alpha subunit in the proliferation of BCR/ABL-dependent cell lines and chronic myelogenous leukemia (CML) primary cells. Similarly, wortmannin, a specific inhibitor of the enzymatic activity of the p110 subunit of PI-3 kinase, inhibited growth of these cells. The growth of normal bone marrow and erythromyeloid, but not megakaryocyte, progenitors was inhibited by p85 alpha antisense [S]ODNs, but wortmannin, at the concentrations tested, did not affect normal hematopoiesis. The proliferation of two BCR/ABL- and growth factor-independent cell lines was not affected by downregulation of the expression of the p85 alpha subunit or inhibition of p110 enzymatic activity, confirming the specificity of the observed effects on Ph1 cells. Thus, PI-3 kinase is one of the downstream effectors of BCR/ABL tyrosine kinase in CML cells. Moreover, reverse transcriptase-polymerase chain reaction performed on single colonies to detect BCR-ABL transcripts showed that wortmannin was able to eliminate selectively CML-blast crisis cells from a mixture of normal bone marrow and Ph1 cells.
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PMID:Phosphatidylinositol-3 kinase activity is regulated by BCR/ABL and is required for the growth of Philadelphia chromosome-positive cells. 760 2

It has been suggested that the BCR-ABL gene of chronic myeloid leukemia (CML) is not uniformly expressed in Philadelphia (Ph)-positive cells, and that BCR-ABL gene expression precludes transcription of the normal BCR or ABL genes. Therefore, we have analyzed granulocyte-macrophage colony-forming unit (CFU-GM) colonies derived from peripheral blood of 11 CML patients by cytogenetic and by reverse transcriptase-polymerase chain reaction (PCR) amplification of BCR-ABL, ABL-BCR, BCR, and ABL. All CFU-GM colonies with analyzable metaphases were found to contain a Ph chromosome. In 2 patients, the initial PCR screening failed to detect BCR-ABL transcripts in 2 of 11 and 1 of 7 Ph-positive colonies. However, when amplification for BCR-ABL was repeated in quintuplicate, all but 1 colony from a single patient showed one or more positive results. Amplifications of the four genes in each colony showed that BCR-ABL, ABL-BCR, and the normal BCR and ABL were simultaneously expressed in the majority of CFU-GM colonies. Replicate PCR tests for BCR and for ABL in colonies initially scored as negative also uncovered previously undetected positive amplifications. We conclude that BCR-ABL expression does not suppress transcription from the normal BCR and ABL genes, and that Ph-positive, BCR-ABL-negative colonies derived from peripheral blood CFU-GM are rare or nonexistent.
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PMID:BCR-ABL, ABL-BCR, BCR, and ABL genes are all expressed in individual granulocyte-macrophage colony-forming unit colonies derived from blood of patients with chronic myeloid leukemia. 1169 40

Genomic imprinting has recently been associated with the reciprocal t(9;22) chromosome translocation of chronic myeloid leukaemia (CML). This translocation gives rise to a 22q-, or Philadelphia (Ph), chromosome and a derivative 9q+. Based on heterochromatin polymorphisms, it was reported that the former is of maternal and the latter of paternal origin in every case of CML. This parental bias led to the hypothesis that the genes disrupted by the translocation, BCR and ABL, were themselves imprinted, and that in CML the BCR-ABL gene was formed by BCR sequences of maternal and ABL sequences of paternal origin. We have identified a BstNl restriction fragment length polymorphism in the ABL coding sequence which enabled us to investigate directly the expression and inheritance of the two ABL alleles in heterozygous CML patients. Amplification of the specific BCR-ABL and normal ABL mRNA messages by reverse transcriptase-polymerase chain reaction in these patients showed that the ABL moiety of the BCR-ABL gene has an even chance of being the paternal or the maternal copy. We conclude therefore that there is no parental bias in the origin of the translocated ABL gene and no evidence for genomic imprinting of ABL in CML.
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PMID:Balanced parental contribution to the ABL component of the BCR-ABL gene in chronic myeloid leukemia. 772 12

alpha-Interferon (IFN) has been used to induce cytogenetic remission in chronic myeloid leukaemia (CML), but there are few indicators to predict IFN response. The role of the chimaeric BCR/ABL gene in the malignant process is undisputed. There are, however, conflicting views as to whether the breakpoint site within the BCR gene, and the type of mRNA produced determine disease prognosis and progression. The function and clinical significance of the newly discovered ABL/BCR mRNA has not been investigated for a correlation with CML prognosis or response to therapy. We have used a two-step reverse transcriptase polymerase chain reaction (RT-PCR) to detect the transcripts of the chimaeric genes BCR/ABL, ABL/BCR, as well as the normal ABL and BCR genes in 24 CML patients treated with IFN. Because of the variable expression of the four transcripts at presentation, a correlation between gene expression, prognosis and clinical progression was examined. No correlation between prognosis and gene expression was seen. Also, no correlation was found between expression of BCR, ABL or BCR/ABL mRNA and response to treatment with IFN. However, 7/10 ABL/BCR mRNA positive patients achieved a major cytogenetic response to IFN; but of the 13 ABL/BCR mRNA negative patients, only two achieved a major cytogenetic response (P = 0.013). Further studies are required to confirm these findings.
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PMID:Interferon response in chronic myeloid leukaemia correlates with ABL/BCR expression: a preliminary study. 773 52

We report the results of consecutive tests in nine BCR-ABL-positive ALL patients by one-step and two-step (nested primer) reverse transcriptase-polymerase chain reaction (RT-PCR). Six patients could be tested in complete haematological remission (CHR). One patient remained one-step positive; four patients became one-step negative, but remained two-step positive; only one patient became two-step negative. In five patients the haematological relapse was preceded by one-step positivity by 1.5-5 weeks. In two patients who received autologous BMT in CHR, BCR-ABL was still detectable by two-step PCR, whereas allogeneic BMT was able to transiently reduce BCR-ABL below the two-step detection level. Our results show that one-step combined with two-step RT-PCR analysis gives valuable information about the efficacy of treatment and the dynamics of the leukaemic clone.
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PMID:PCR-monitoring of minimal residual leukaemia after conventional chemotherapy and bone marrow transplantation in BCR-ABL-positive acute lymphoblastic leukaemia. 777 40

A patient with accelerating Ph+ve chronic granulocytic leukaemia (CGL) was considered for autologous BMT using marrow 'purged' by 4 weeks long-term culture (LTC). Efficacy of purging was determined using reverse transcriptase PCR for BCR-ABL mRNA transcripts b2a2 and b3a2. Peripheral blood and bone marrow were compared. Three observations emerged: (i) the initial b2a2:b3a2 ratios for unmanipulated blood and marrow were different with values of 9:1 and 2:1 respectively; (ii) both transcripts were successfully 'purged' with LTC of blood but not marrow; and (iii) LTC of marrow caused a transient increase in relative levels of b3a2 mRNA and a corresponding reduction in the b2a2 signal. This is the first case where such differences have been demonstrated in association with LTC.
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PMID:Long-term culture and molecular biological studies highlight differences in relative BCR-ABL expression levels in the peripheral blood and bone marrow of a patient with chronic granulocytic leukaemia. 780 92

Interferon-alpha induces durable cytogenetic remissions in about one-quarter of newly diagnosed patients with chronic myelogenous leukemia (CML). Even so, after short-term follow-up, previous studies have shown that residual leukemic cells can be detected by the polymerase chain reaction (PCR) in all of these individuals. The objectives of our study were therefore to obtain long-term follow-up data on residual disease in a cohort of complete responders and to determine if leukemic cells with clonogenic potential are present in patients despite the absence of relapse. We performed (a) serial analysis of blood and/or bone marrow for a reverse transcriptase PCR amplified BCR-ABL transcript at times well beyond the point that cytogenetic remission was first attained and (b) reverse transcriptase PCR of individually plucked myeloid and erythroid colonies for the presence of the same transcript. Seven CML patients who had previously attained complete cytogenetic remission while on interferon-alpha were investigated. Six of the seven patients were in complete cytogenetic remission at the time of analysis, whereas one patient had early evidence of cytogenetic relapse. With ongoing therapy, five patients with the longest follow-up eventually achieved PCR negativity at time periods of 27, 32, 36, 49, and 67 mo after a complete cytogenetic remission was first noted. Even so, residual disease was detected in progenitor cells derived from two patients, each of whom had been in continuous cytogenetic remission for approximately 2.5 and 3.5 yr, respectively. Progenitors expressing BCR-ABL transcripts were also detected in the patient with early cytogenetic relapse. These observations demonstrate that residual disease resides in colony-forming cells that should have the potential to repopulate the bone marrow. However, the presence of a minority of Ph-positive CML progenitor cells for a very long period of time is still compatible with durable remission, confirming that a situation of tumor dormancy may be induced in CML by interferon therapy.
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PMID:Persistence of dormant leukemic progenitors during interferon-induced remission in chronic myelogenous leukemia. Analysis by polymerase chain reaction of individual colonies. 792 13


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