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:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

BCR-ABL is a chimeric oncogene generated by translocation of sequences from the c-abl protein-tyrosine kinase gene on chromosome 9 into the BCR gene on chromosome 22. Alternative chimeric proteins, p210BCR-ABL and p190BCR-ABL, are produced that are characteristic of chronic myelogenous leukemia and acute lymphoblastic leukemia, respectively. Their role in the etiology of human leukemia remains to be defined. Transformed murine hematopoietic cells can be used as a model of BCR-ABL function since these cells can be made growth factor independent and tumorigenic by the action of the BCR-ABL oncogene. We show that the BCR-ABL oncogenes prevent apoptotic death in these cells by inducing a Bcl-2 expression pathway. Furthermore, BCR-ABL-expressing cells revert to factor dependence and nontumorigenicity after Bcl-2 expression is suppressed. These results help to explain the ability of BCR-ABL oncogenes to synergize with c-myc in cell transformation.
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PMID:Tumorigenic activity of the BCR-ABL oncogenes is mediated by BCL2. 777 99

The bcr-abl oncogene is a fusion gene resulting from a reciprocal translocation which forms the hallmark of chronic myeloid leukemia (CML). Antisense oligonucleotides complementary to the two possible mRNA breakpoints were found to inhibit cell growth of CML patient cells and cell lines, but doubt exists about their specificity. In order to test the specificity, phosphorothioate and 3' phosphorothioate capped antisense BCR-ABL oligonucleotides of different length were used. Stability, cellular uptake of oligonucleotides and effect on cell growth were studied in two CML cell lines, BV173 and LAMA-84. Phosphorothioate antisense BCR-ABL oligonucleotides were most stable, showed the highest uptake and induced cell death in BV173 but not in LAMA-84 cells. We selected the most effective antisense oligonucleotide for further analysis. The BV173 and LAMA-84 cell lines do not express the normal c-abl protein, we therefore used a c-abl specific monoclonal antibody for the detection of p210bcr-abl expression by flow cytometry. Dead cells found after treatment were gated out of analysis. Although BCR-ABL antisense oligonucleotides can induce apoptosis, no reduction of p210bcr-abl levels could be detected in living cells after treatment with antisense oligonucleotides. We conclude that antisense mediated inhibition of translation of mRNA into p210bcr-abl is not the mechanism responsible for the induction of apoptosis in cell line BV173.
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PMID:Phosphorothioate BCR-ABL antisense oligonucleotides induce cell death, but fail to reduce cellular bcr-abl protein levels. 784 6

Philadelphia (Ph)-positive leukemias invariably contain a chromosomal translocation fusing BCR to ABL. The BCR-ABL protein is responsible for leukemogenesis. Here we show that exposure of bcr-null mutant mice to gram-negative endotoxin led to severe septic shock and increased tissue injury by neutrophils. Neutrophils of bcr (-/-) mice showed a pronounced increase in reactive oxygen metabolite production upon activation and were more sensitive to priming stimuli. Activated (-/-) neutrophils displayed a 3-fold increased p21rac2 membrane translocation compared with (+/+) neutrophils. These results connect Bcr in vivo with the regulation of Rac-mediated superoxide production by the NADPH-oxidase system of leukocytes and suggest a link between Bcr function and the cell type affected in Ph-positive leukemia.
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PMID:Increased neutrophil respiratory burst in bcr-null mutants. 788 65

We report a girl with Ph1-positive ALL with the aberrant BCR-ABL product. In this case, bcr exon 3 jointed not to ordinal abl exon 2 but to exon 3 resulting in the production of a 203 kD BCR-ABL fusion protein with marked tyrosine kinase activity. To our knowledge, this is the first report of an aberrant BCR-ABL product in childhood. This case was characterized with younger age and low leucocyte count at the onset, but relapsed early like the typical Ph1-positive ALL, suggesting the diversity in the clinicopathogenesis of Ph1-positive ALL.
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PMID:A novel 203 kD aberrant BCR-ABL product in a girl with Philadelphia chromosome positive acute lymphoblastic leukaemia. 791 54

In view of the elevated risk of leukemia among A-bomb survivors, genetic alterations associated with Leukemia can be considered to have been induced by ionizing radiation. Therefore, to clarify this possibility, an examination was made to see whether genetic changes such as BCR-ABL translocation closely associated with chronic myelogenous leukemia (CML) are actually induced by radiation. BCR-ABL translocation is easily detected by means of reverse transcription polymerase chain reaction. One hundred million cells of the promyelocytic leukemia-derived cell line HL60, which do not have such a gene rearrangement, were irradiated with 100 Gy of X-ray, after which RNA was extracted and examined for any rearrangements of BCR and ABL genes. Five kinds of bands were observed in the HL60 cells irradiated with 100 Gy of X-ray, and it became clear that these positive bands contain both BCR gene and ABL gene by the direct sequencing method. Furthermore, these gene rearrangements included not only the rearrangements specifically identified with CML but also atypical rearrangements which are not generally observed clinically. The induction by X-irradiation of such gene changes characteristic of malignant tumors, which are closely associated with radiation carcinogenesis, suggests that they are the initial gene changes in radiation carcinogenesis.
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PMID:[Gene rearrangement and radiation carcinogenesis]. 802 92

Cytogenetic analysis of a pediatric patient with T-cell acute lymphoblastic leukemia (T-ALL) revealed a mosaic karyotype, 47,XX,+17,t(11;14)(p13;q11)/47,XX,+17,t(9;22)(q34;q11),t(11;14) (p13;q11). DNA blot analysis was used to examine the break-point within the BCR gene on chromosome 22 and showed that the breakpoint occurred within the 20-kb minor breakpoint cluster region (m-bcr) located within the first intron of the BCR gene. Immunoprecipitation analysis demonstrated that the leukemic cells expressed the P185 BCR-ABL protein tyrosine kinase. P185 BCR-ABL has previously been shown to be expressed in most cases of Ph+ acute leukemia of myeloid and B-progenitor origin. Here, we demonstrate for the first time that P185 can also be expressed in the T-cell lineage. DNA blot hybridization was also used to characterize the t(11;14) translocation. This showed rearrangement on chromosome 11 within the T-ALLbcr region, upstream of the RBTN-2 gene. Polymerase chain reaction revealed the presence of RBTN-2 transcripts in the leukemic cells. Finally, comparison of the T-ALLbcr, BCR-ABL, IGH, TCR beta and gamma gene rearrangements in leukemic cells obtained at the time of diagnosis and at first relapse showed that relapse occurred in a leukemic clone indistinguishable from the major Ph+ clone involved at diagnosis. Together, these data support a multistep pathogenesis in which the Philadelphia (Ph) chromosome translocation appeared subsequent to the +17 and t(11;14) and imparted a growth advantage over the Ph-negative cells that carried these abnormalities.
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PMID:Simultaneous expression of RBTN-2 and BCR-ABL oncogenes in a T-ALL with a t(11;14)(p13;q11) and a late-appearing Philadelphia chromosome. 803 4

The pH chromosome, resulting from the t(9;22) translocation, is the most frequently observed cytogenetic aberration in acute lymphoblastic leukemia (ALL). Two genes, bcr and abl, are involved in this translocation. As a consequence, parts of the bcr and abl genes are fused, resulting in chimeric bcr-abl genes encoding chimeric BCR-ABL proteins. Three bcr-abl genes and proteins have been identified: e1-a2 P190bcr-abl, b2-a2 P210bcr-abl, and b3-a2 P210bcr-abl. Since these chimeric proteins only occur in Ph-chromosome-positive leukemic cells, they are by definition tumor-specific markers. Ph-chromosome-positive ALL is correlated with a bad prognosis, therefore the detection of chimeric BCR-ABL proteins is of prime importance in ALL diagnosis. In the present study, we report on the generation of a monoclonal antibody termed ER-FP1, raised against the tumor-specific e1-a2 BCR-ABL junction in P190bcr-abl. We show that ER-FP1 reacts highly specifically with e1-a2 P190bcr-abl in different assays. The reactivity of ER-FP1 with e1-a2 P190bcr-abl in soluble form was analyzed in an immunoprecipitation assay; specificity was confirmed by peptide inhibition studies. Binding of ER-FP1 to e1-a2 P190bcr-abl at the single cell level was detected by using immunofluorescence techniques. Immunological double-staining experiments using ER-FP1 and a monoclonal antibody recognizing all BCR-ABL proteins confirmed the specificity of ER-FP1 for the e1-a2 fusion point.
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PMID:Recognition of the ALL-specific BCR-ABL junction in P190bcr-abl by monoclonal antibody ER-FP1. 809 30

A case with typical features of chronic myelogenous leukemia (CML) with two complex aberrations in addition to the standard t(9;22) is reported. Cytogenetic evaluation of the patient's bone marrow cells (BMC) showed 46,XX,t(6;19)(q16;p13.3),t(9;22)(q34;q11) in 60% of the mitotic cells and 46,XX,idem, t(6;15)(p25;q22) in the remaining 40% dividing cells. The patient's peripheral blood smear exhibited the usual differential observed in chronic-phase CML and was clinically indistinguishable from patients with the t(9;22) as the only translocation. We performed Southern blotting on BglII-digested DNA with the Trans-Probe (OSI) and in addition to the 4.8-, 2.3-, and 1.1-kilobase (kb) germline fragments, we detected an additional fragment at 7 kb. This probe spans the entire 5.8-kb M-breakpoint cluster region (BCR), and a single breakpoint in this region will appear as either one or two additional fragments. Because only one additional fragment was observed, both cell lines apparently share the same breakpoint in the ABL/BCR gene. Apparently the second aberrant cell line with the additional t(6;15) represents clonal evolution of the original abnormal clone.
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PMID:New translocations [t(6;15)(p25;q22) and t(6;19)(q16;q13.3)] with t(9;22)(q34;q11) in a Ph-positive chronic myelogenous leukemia. 811 41

We used fluorescence in situ hybridization (FISH) to metaphase chromosomes with BCR and ABL cosmid probes in conjunction with the polymerase chain reaction (PCR) to study the mechanism by which the ABL proto-oncogene is inserted into a morphologically normal chromosome 22 in patients with Ph-negative chronic myeloid leukaemia characterized by the BCR-ABL chimeric gene. In control patients with Ph-positive CML the ABL probe localized to 22q- and the 3' BCR probe localized to 9q+. In nine Ph-negative CML patients the ABL probe localized to one normal chromosome 9 and to one 'normal' chromosome 22. Both 5' and 3' BCR probes localized exclusively to the chromosomes 22. By PCR all had evidence of BCR-ABL transcripts, but none had evidence of the reciprocal ABL-BCR gene product that is seen in 70% of the Ph-positive CML patients. These data confirm the view that Ph-negative CML results from insertion of ABL-containing DNA sequences into a normal-appearing chromosome 22 without reciprocal translocation of sequences from chromosome 22 to chromosome 9.
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PMID:Lack of reciprocal translocation in BCR-ABL positive Ph-negative chronic myeloid leukaemia. 812 50


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