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)

Chronic myelogenous leukemia (CML) is characterized cytogenetically by the presence of the Philadelphia chromosome, which is the result of a reciprocal translocation between chromosomes 9 and 22. Analysis of the rearranged chromosome 22 have demonstrated that the DNA breakpoints fall within a 5.8-kilobase (kb) region termed M-bcr. In Ph1-acute lymphocytic leukemia, approximately half of the patients have a breakpoint within M-bcr, whereas the remaining half have the break within the first intron of the BCR gene (m-bcr). We have investigated five cases with CML in the blastic phase to search the molecular mechanism of blastic crisis in CML. Using a method of reverse transcriptase-polymerase chain reaction (RT-PCR), we have identified both types of breakpoints in samples of the three cases, suggesting the existence of M-bcr/ABL and m-bcr/ABL chimeric mRNAs in the RNA samples derived from blasts of the three cases. We have further analysed for alterations in the p53 gene in those cases. The p53 gene is now considered to be a tumor suppressor gene and its mutations play a role in the development of many human malignancies. We have attempted to determine whether the p53 gene is involved in the mechanism of blastic crisis in CML. Using the methods of RT-PCR and single stand-conformational polymorphism (SSCP), we have detected expression of only a mutated p53 allele in a case with CML blastic crisis, indicating that inactivation of the p53 gene in both alleles may contribute to the blastic crisis in this case. Accumulation of molecular analysis in more cases will clarify the mechanism of blastic crisis in CML.
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PMID:[Analysis of Ph1-positive leukemia by PCR]. 206 73

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

hLH-2, a transcription factor that contains double cysteine rich regions (LIM motifs) and a homeobox (Hox) DNA-binding domain shows aberrant high expression in all cases of chronic myelogenous leukemia (CML). This gene has been mapped to the chromosome 9q33-34.1, the same region as the reciprocal translocation that creates the breakpoint cluster region (BCR)-ABL chimera of the Philadelphia chromosome (Ph'). To investigate the possible involvement between the BCR-ABL fusion gene and hLH-2 in the pathogenesis of CML, an hLH-2-negative CML cell line, JK-1 that carries double Ph' chromosomes, was examined. Like other CML cells, high BCR-ABL fusion mRNA levels are expressed, but no transcript of hLH-2 was detected in JK-1 cells as determined by reverse transcriptase-polymerase chain reaction (RT-PCR). Compared with the CML cell line, K-562, an additional rearrangement of the BCR gene was observed in JK-1 as determined by Southern blot hybridization; however, the hLH-2 gene was normal. These findings raise interesting questions about the possible roles of either the abnormal BCR gene or other genetic events such as the complex chromosomal abnormalities that result in hLH-2 being turned off in JK-1 cells.
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PMID:A structurally abnormal breakpoint cluster region gene in a transcription factor, hLH-2-negative human leukemia cell line. 760 May 33

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

A newly established human leukemia cell line, OM9;22, is reported, with B-precursor immunophenotype (CD10+ CD19+ CD22+ HLA- DR+ C mu-) and CD13 antigen, originated from a 19-year-old female patient with Philadelphia (Ph) chromosome-positive acute lymphoblastic leukemia (ALL). The OM9;22 cells carry a Philadelphia (Ph) translocation and hybrid message detected by a minor-breakpoint cluster region (BCR) exon 1/ABL exon 2 junctional probe using reverse transcriptase polymerase chain reaction. The genetic alterations are consistent with those observed in the donor's leukemia cells, allowing us to conclude that this cell line is a minor-BCR rearranged Ph-positive ALL (Ph+ ALL). Colony formation of the OM9;22 cells in methylcellulose culture is enhanced by the addition of human interleukin 7 (IL-7). In liquid culture, more than 80% of IL-7-treated OM9;22 cells express CD20 antigen but fail to express surface immunoglobulins or cytoplasmic mu-chain, indicating that the cells have a potential of limited maturation by IL-7. By contrast, IL-4 suppresses the colony formation of the OM9;22 cells. These findings suggest that this cell line might be a model of B-precursor human leukemia with proliferative capability by IL-7.
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PMID:Interleukin-7 enhances colony growth and induces CD20 antigen of a Ph+ acute lymphoblastic leukemia cell line, OM9;22. 768 4

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


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