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)

We report the case of a patient having Philadelphia-negative, bcr-abl-positive chronic myeloid leukemia. In situ hybridization showed the presence of the bcr-abl fusion on the chromosome 9 long arm in all mitoses observed. Stability of the disease was very difficult to obtain because of serious adverse effects to interferon and chemotherapy, mainly grade IV neutropenia, and a blast crisis occurred 12 months after diagnosis. Only three other patients with such presentation (Philadelphia negative, bcr-abl positive with bcr-abl fusion on the chromosome 9 long arm) have been reported, with a poor therapeutic response and outcome in two of them. Translocation of BCR to chromosome 9 may therefore have a worse prognosis than translocation of ABL to chromosome 22 in Philadelphia-negative chronic myeloid leukemia.
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PMID:Translocation of BCR to chromosome 9 in a Philadelphia-negative chronic myeloid leukemia. 853 45

The BCR gene is implicated in the development of Ph-positive leukemia through its fusion with the nonreceptor tyrosine kinase gene ABL. The normal 160 kDa Bcr protein has several functional domains, and recently one specific role for Bcr was established in the regulation of respiratory burst activity in white blood cells. Bcr expression levels are relatively constant throughout mouse development until adulthood in brain and in hematopoietic tissues, a pattern that is distinctly different from that of the functionally related n-chimerin gene. In the present study, RNA in situ hybridization was used to explore the normal cellular function of Bcr in rodent brain and hematopoietic organs. The data pinpoint the high bcr expression in the brain to the hippocampal pyramidal cell layer and the dentate gyrus, and to the piriform cortex and the olfactory nuclei, reflecting a potentially interesting function for Bcr in these highly specialized brain regions.
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PMID:Regional localization and developmental expression of the BCR gene in rodent brain. 858 Oct 68

Interferon-alpha (IFN-alpha) is useful in the treatment of Philadelphia (Ph)-positive chronic myeloid leukaemia (CML). There is, however, a marked heterogeneity among CML patients in relation to their response to IFN-alpha treatment, the reasons for which are unknown. Since the reciprocal ABL-BCR gene is transcriptionally active in only a proportion of CML patients, it has been suggested that response to IFN-alpha may correlate with ABL-BCR expression. In the present study we have tested 209 Ph-positive CML patients for expression of ABL-BCR, BCR-ABL and the normal BCR and ABL genes by reverse transcriptase/polymerase chain reaction (RT/PCR). Whereas BCR-ABL, BCR and ABL transcripts were detected in all the patients, ABL-BCR expression was observed in 59% of the cases. A group of 105 patients within this series was treated with IFN-alpha; 33% achieved a complete or major cytogenetic response (< 35% Ph-positive metaphases) and the remaining 67% showed minimal or no response to IFN-alpha. The proportions of patients who were ABL-BCR positive (63%) and ABL-BCR negative (37%) were the same for good responders and poor responders, suggesting that there is no correlation between ABL-BCR expression and cytogenetic response to IFN-alpha in CML.
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PMID:Lack of correlation between ABL-BCR expression and response to interferon-alpha in chronic myeloid leukaemia. 861 36

The first exon of the BCR gene encodes a new serine/threonine protein kinase. Abnormal fusion of the BCR and ABL genes, resulting from the formation of the Philadelphia chromosome (Ph), is the hallmark of Ph-positive leukemia. We have previously demonstrated that the Bcr protein is tyrosine phosphorylated within first-exon sequences by the Bcr-Abl oncoprotein. Here we report that in addition to tyrose 177 (Y-177), Y-360 and Y283 are phosphorylated in Bcr-Abl proteins in vitro. Moreover, Bcr tyrosine 360 is phosphorylated in vivo within both Bcr-Abl and Bcr. Bcr mutant Y177F had a greatly reduced ability to transphosphorylate casein and histone H1, whereas Bcr mutants Y177F and Y283F had wild-type activities. In contrast, the Y360F mutation had little effect on Bcr's autophosphorylation activity. Tyrosine-phosphorylated Bcr, phosphorylated in vitro by Bcr-Abl, was greatly inhibited in its serine/threonine kinase activity, impairing both auto- and transkinase activities of Bcr. Similarly, the isolation of Bcr from cells expressing Bcr-Abl under conditions that preserve phosphotyrosine residues also reduced Bcr's kinase activity. These results indicate that tyrosine 360 of Bcr is critical for the transphosphorylation activity of Bcr and that in Ph-positive leukemia, Bcr serine/threonine kinase activity is seriously impaired.
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PMID:Inhibition of Bcr serine kinase by tyrosine phosphorylation. 862 3

To test whether patients in remission after allogeneic bone marrow transplantation (BMT) possess a pool of chronic myeloid leukemia (CML) cells that do not express BCR-ABL mRNA, we have compared the results and sensitivity of amplification of BCR-ABL from genomic DNA with conventional reverse transcription-polymerase chain reaction (RT-PCR). Bubble PCR was used to amplify the genomic BCR-ABL translocation breakpoints from chronic-phase DNA of 10 patients with CML who subsequently underwent BMT. After cloning and sequencing of the amplification products, patient-specific ABL primers were synthesized and tested for both specificity and sensitivity in nested or heminested combinations with a variety of primers derived from the major breakpoint cluster region of the BCR gene. In all cases, combinations of primers were selected that enabled the detection of chronic-phase DNA from a specific patient at up to a 10(5)x dilution into DNA from a normal individual. Patterns of residual disease obtained by serial RT-PCR and DNA-PCR analyses of blood and bone marrow samples obtained after BMT were similar for most patients, including one treated for relapse by infusion of donor leukocytes. Of the 24 samples for direct comparison of RT-PCR and DNA-PCR, results were concordant in 19 (79%) cases. Five results were discordant. In two instances, RT-PCR was positive, while PCR from genomic DNA was negative; this discrepancy might have arisen due to the slightly greater sensitivity of RT-PCR compared with DNA-PCR. In three samples from three patients, two of whom had been transplanted in the accelerated phase, PCR from genomic DNA was positive while RT-PCR was negative; this could mean that some CML cells in these samples had a reduced or absent capacity to express BCR-ABL mRNA post-transplant. Of these three patients, one subsequently relapsed; and two are in remission at 21 and 24 months after the discordant result. Thus, the finding of a single DNA-PCR- positive, RT-PCR-negative results does not necessarily predict relapse. Because the great majority of samples (79%) gave concordant results with the two assays, we believe that patients in remission do not generally harbor a substantial pool of CML cells that do not express BCR-ABL mRNA.
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PMID:Comparison of genomic DNA and cDNA for detection of residual disease after treatment of chronic myeloid leukemia with allogeneic bone marrow transplantation. 863 Apr 27

In Philadelphia chromosome (Ph1) positive leukemias, the BCR gene is fused to the ABL gene. The resulting chimeric BCR-ABL oncoproteins are thought to play a central role in the pathogenesis of these diseases. We previously described two exons that can be spliced alternatively to the second BCR exon in place of the first exon to form minor messages. In this paper, we localize the alternative exons to a 4.1 kb BglII fragment in the 5' region of the large first intron of the BCR gene. This genomic structure is of interest because of its analogy to the organization of the ABL gene and because this part of the gene is not affected by the breakpoints occurring in Ph1-positive acute lymphoblastic leukemia (ALL). Using the reverse transcriptase-polymerase chain reaction (RT-PCR), we detected the alternative messages in all cases of chronic myelogenous leukemia (CML) tested, including seven samples in the chronic phase, five in the accelerated phase and nine in the acute phase, as well as in the majority of other samples studied. These findings suggest a functional role for the variant transcripts.
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PMID:The first intron of the BCR gene contains two minor alternative exons. 863 66

The incidence and clinical relevance of the Philadelphia (Ph) translocation t(9:22) (q34:q11) in T-lineage acute lymphoblastic leukaemia (ALL) are unknown. We describe a patient with pre-T-ALL and a clonal 22q-aberration detected by conventional cytogenetics, suggestive of a Ph translocation. However, fluorescence in situ hybridization (FISH) using BCR and ABL probes revealed a translocation with one breakpoint within the BCR gene on chromosome 22 without juxtaposition of ABL on chromosome 9. We discuss the diagnostic and possible pathogenetic implications of this Ph-like chromosomal aberration.
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PMID:BCR rearrangement without juxtaposition of ABL in pre-T acute lymphoblastic leukaemia. 863 38

Chronic myelogenous leukaemia (CML) is associated with a translocation between the ABL and BCR genes on chromosomes 9 and 22, t(9;22). The resulting transcription and translation products, bcr-abl mRNA and p210bcr-abl, are unique to the malignant cells and as such are ideal targets for specific chemicals or drugs. We have designed hammerhead ribozymes to cleave the two predominant forms of bcr-abl mRNA, b2a2 and b3a2. Synthetic bcr-abl RNA substrates were cleaved by the ribozymes in vitro, but so was a wild-type abl RNA sequence. bcr RNA was not cleaved in vitro and mutant ribozymes showed no cleavage activity. Ribozymes designed to cleave 9 nucleotides (nt) from either of the fusion points were non-specific for the bcr-abl substrate, but a ribozyme designed to cleave 3 nt upstream of the b3a2 fusion point was specific for b3a2 RNA. However, this ribozyme was less efficient than the others. The shortening of one of the ribozymes arms from 10 nt to 4 nt resulted in a ribozyme that was more specific without losing any efficiency. We conclude that it is possible to specifically cleave bcr-abl RNA in vitro by using hammerhead ribozymes.
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PMID:Investigating and improving the specificity of ribozymes directed against the bcr-abl translocation. 884 9

Acyclovir (ACV), a nucleoside analog, has been demonstrated previously to suppress selectively the proliferation of NIH3T3 fibroblastic cells transformed by either v-abl or bcr-abl gene transfection. From a viewpoint of clinical application of ACV, we investigated whether ACV inhibited the growth of leukemia cells expressing either p210 BCR-ABL or p185BCR-ABL. Acyclovir exerted an inhibitory effect on OM9;22 cells, p185BCR-ABL expressing cells, in a dose-dependent manner. Despite no down-modulation of a BCR-ABL tyrosine kinase activity or its expression was observed after treatment with ACV, cell cycle analysis demonstrated synchronization of OM9;22 cells at the G0/G1 phase. This suggests that, although ACV does not directly act on BCR-ABL tyrosine kinase, ACV may exert its inhibitory effect on some leukemia cell lines via alterations of the cell cycle. Although selective inhibition of Philadelphia chromosome-positive leukemia cell growth was not apparent, our data provides a therapeutic possibility for ACV in the treatment for leukemia.
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PMID:Inhibitory effect of a nucleoside analog, acyclovir, on leukemia cells. 868 81

The Philadelphia chromosome (Ph) resulting from translocation t(9;22)(q34;q11) is observed in more than 90% of patients with chronic myeloid leukemia (CML). Its molecular consequence is the genesis of a fusion gene BCR-ABL between the 5' sequences of the BCR gene (chromosome 22) and the 3' end of the ABL gene (chromosome 9). Fluorescence in situ hybridization (FISH) using specific DNA probes provides a useful tool for the detection of t(9;22) and BCR-ABL rearrangement. We report our results using the FISH technique for t(9;22) assessment in the hematopoietic cells of patients with Ph-positive CML. The DNA libraries pBS 9 and pBS 22 containing multiple sequences derived from chromosomes 9 and 22 have been used to identify t(9;22) in metaphase cells. The cos bcr-51 and cos abl-18 probes that hybridize to unique sequences specific to the BCR and ABL genes have the ability to detect the BCR-ABL rearrangement in metaphase cells as well as in interphase nuclei. FISH is a sensitive and specific technique that represents a valuable complement to conventional cytogenetics. The BCR-ABL rearrangement can be detected in metaphase spreads of insufficient quality or from interphase nuclei in the case of terminally differentiated cells or of cells which do not divide in vitro. When the efficiency of hybridization and detection is good, a large number of cells can be analyzed. This is of major significance in assessment of response to treatment and definition of a cytogenetic remission. However, interphase cytogenetics may be difficult due to variations in signal resolution and background level. The FISH technique can also be used to detect the BCR-ABL rearrangement in cases of Ph negative BCR-ABL positive CML.
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PMID:[Fluorescent in-situ hybridization technique (FISH) in the diagnosis of Philadelphia translocation in chronic myeloid leukemia]. 868 81


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