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)

The Philadelphia chromosome (Ph) is the cytogenetic hallmark of chronic myeloid leukemia (CML) and as such has been used to confirm the diagnosis of CML based on morphological and clinical criteria. We have investigated 12 patients who were considered to have clinical and morphological features of CML and who did not have detectable abnormalities of chromosomes 9q34 or 22q11. In six of the 12 patients, rearrangement within the 5.8 kb major breakpoint region (M-bcr) and amplification of CML specific M-bcr-ABL cDNA sequences by the polymerase chain reaction (PCR) was demonstrated. Six other CML patients did not have rearrangement of the M-bcr gene or amplification of BCR-ABL by PCR. These patients had atypical CML. They were significantly older, most had less than 10% immature granulocytic cells (metamyelocytes, myelocytes and promyelocytes) and had various degrees of marrow fibrosis. Three of these six patients died of blastic transformation at 4, 15 and 54 months from diagnosis.
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PMID:Molecular diagnosis of Philadelphia negative CML using the polymerase chain reaction and DNA analysis: clinical features and course of M-bcr negative and M-bcr positive CML. 201 77

The Philadelphia translocation in chronic myelogenous leukemia (CML) results in the production of a 210 kD BCR-ABL protein. In contrast, in 50% of Philadelphia-positive acute leukemias, the translocation results in the production of a 190 kD BCR-ABL protein. To investigate the hypothesis that the production of P190 may be associated with the progression from chronic phase to blast crisis in CML, we used polymerase chain reaction to analyze blood from 37 patients with accelerated phase/blast crisis CML for the transcripts coding for the P210BCR-ABL and P190BCR-ABL. The mRNA encoding for P210 was detected in all patients. In three patients, mRNA encoding both P210 and P190 was present. In two of these three patients, samples were available from the time of initial diagnosis. Analysis of these samples did not reveal any transcripts for P190. We conclude that in some patients the appearance of P190BCR-ABL may correlate with transformation to a more aggressive, terminal phase of CML.
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PMID:Appearance of acute leukemia-associated P190BCR-ABL in chronic myelogenous leukemia may correlate with disease progression. 201 78

More than 95% of patients with chronic myelogenous leukemia (CML) contain an abnormal chromosome termed the Philadelphia chromosome (Ph1). Ph1 and the resulting BCR-ABL fused genes are markers for this type of leukemia. The product of the fused BCR-ABL genes is a protein of about 2000 amino acids termed P210 BCR-ABL. Although the BCR-ABL protein can be routinely detected in blood cells from blast crisis CML patients by assaying for its activated tyrosine kinase activity, detection of P210 BCR-ABL in early stage CML patients (chronic phase) has not yet been possible (S. A. Maxwell et al., Cancer Res., 47: 1731, 1987). A procedure involving Western blotting with an anti-ABL monoclonal antibody was developed that allows detection of P210 BCR-ABL and P145 ABL in cells from chronic phase and blast crisis CML patients, but as expected only P145 ABL was found in normal white blood cells. Most chronic phase patients also contained one to two ABL proteins with a molecular weight of about 190,000. Interestingly, the ratio of BCR-ABL to ABL proteins increased in four blast crisis patients compared to 18 chronic phase patients. Also, one chronic phase patient analyzed on three separate occasions lacked P210 BCR-ABL and exhibited only the Mr 190,000 form. This assay should also be useful in other leukemias that express altered forms of the ABL protein.
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PMID:Detection of BCR-ABL proteins in blood cells of benign phase chronic myelogenous leukemia patients. 203 43

The Ph chromosome was the first specific karyotype abnormality associated with a particular neoplastic disease in humans. For many years it was suspected that chromosome abnormalities might cause cancer by alteration of specific genes or their expression. Significant recent developments in our understanding of the molecular consequences of the Ph translocation strengthen that assumption. The Ph translocation generates a hybrid gene consisting of 5' regulatory, promotor, and exon sequences of the bcr gene on chromosome 22 fused to 3' exons and polyadenylation/termination sequences of the ABL proto-oncogene from chromosome 9. It is well established that fusion of bcr and abl genes plays a crucial role in the pathogenesis of CML and ALL. Molecular methods can therefore be used as diagnostic tools to detect the Ph chromosome. Presently, the model of oncogenesis provided by our knowledge of how the abl proto-oncogene becomes activated as a result of the Ph translocation is one of the clearest models of oncogene activation. Despite the progress made, many areas remain to be explored. One important question is, how the hybrid protein is involved in leukemia. Research aimed at investigating the normal function of abl and bcr may be important in efforts to understand their abnormal functioning in leukemia and to increase our understanding of the disease.
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PMID:Molecular insights into the Philadelphia translocation. 205 Jun

In 1960, Nowell and Hungerford found, for the first time, a minute chromosome at the metaphase in chronic myelocytic leukemia (CML) cells, which was called Philadelphia chromosome (Ph1 chromosome) later. Ph1 chromosome was considered to be specific for the disease and was frequently used as an important marker for the definite diagnosis. However, in mid-1970s, some cases with acute lymphocytic leukemia (ALL) were also found to have Ph1 chromosome in the leukemic cells. Therefore, Ph1 chromosome seemed to be non-specific for the diagnosis of CML. In 1980s, molecular-biology techniques were applied in the fields of leukemia research. As a result, clear differences were demonstrated between the two diseases (CML and ALL with Ph1 chromosome, respectively) at the molecular level using oncogene concept. In this review, molecular-genetic constructions of ABL, BCR and BCR-ABL hybrid genes in CML, as well as m-BCR-ABL hybrid gene in Ph1 positive ALL are focused in detail. Relationship between these molecular-genetic changes with the clinical features and the mechanism of cell growth in these cells with BCR-ABL or m-BCR-ABL hybrid genes are also discussed.
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PMID:[Molecular construction of Philadelphia chromosome and its relation to the clinical features]. 205 68

Cytogenetic and molecular aspects of Ph-positive leukemia are described in comparison with those of Ph-positive CML. Chromosomal characteristics of Ph+AL are; 1) mixture of a normal karyotype at diagnosis, 2) frequent combination with +Ph, +21, +6, +8, or -7, 3) recovery of a normal karyotype at remission. Additional chromosome changes at myeloid blast crisis (BC) of CML are characterized by +Ph, i(17q), +8, or +19. Meanwhile, lymphoid BC exhibits +Ph, +21, but not i(17q) or +19. There seems no cytogenetic difference between Ph+AL and lymphoid BC of CML, but i(17q) may be specific for CML BC. Eight patients with Ph+AL were studied with pulsed-field gel electrophoresis (PFGE) to examine the break site within ABL and BCR genes. One case had a M-BCR rearrangement and the remainder a rearrangement upstream of M-BCR. Minor-BCR rearrangement occurs seldom in CML but is detected in approximately a half of the reported cases of Ph+AL. ABL was rearranged within 1st or 2nd intron in all 8 cases. ABL breakpoints appear randomly distributed between exons 1b and 2 in both Ph+AL and CML.
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PMID:[Cytogenetic and molecular aspects of Ph-positive leukemia]. 206 72

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

The characteristic genetic exchange in chronic myeloid leukemia (CML) is the fusion of the ABL proto-oncogene and a specific part of the BCR or phl gene. Detection of this exchange by cytogenetic or Southern blot analysis is highly diagnostic for CML. The latter approach has not previously been used to quantify the relative proportions of leukemic and non-leukemic cells. We have assessed the feasibility of estimating the relative proportion of leukemic cells present in a sample by densitometric analysis of autoradiographs of Southern blots. In dilution experiments of CML cells with normal cells, a linear relationship could be demonstrated between the relative intensity of the autoradiograph band corresponding bcr rearrangement and the proportion of leukemic cells present. This relationship was found to be largely independent of autoradiograph exposure time. Six patients receiving various therapies have been evaluated for as long as 4.5 years by repeated densitometric and cytogenetic analysis. In general, a declining proportion of Philadelphia (Ph) chromosome positive cells was paralleled by decreasing intensity of the autoradiograph band representing bcr rearrangement. Densitometric changes were often seen prior to the detection of Ph negative cells. This analysis appears to provide a sensitive method for monitoring patients with CML.
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PMID:Densitometric analysis of Southern blot autoradiographs and its application to monitoring patients with chronic myeloid leukemia. 207 39

Bovine X hamster hybrid somatic cells have been used to investigate the syntenic relationship of nine loci in the bovine that have homologous loci on human chromosome 9. Six loci, ALDH1, ALDOB, C5, GGTB2, GSN, and ITIL, were assigned to the previously identified bovine syntenic group U18 represented by ACO1, whereas the other three loci, ABL, ASS, and GRP78, mapped to a new, previously unidentified autosomal syntenic group. Additionally, a secondary locus, ABLL, which cross-hybridized with the ABL probe, was mapped to bovine syntenic group U1 with the HSA 1 loci PGD and ENO1. The results predict that ACO1 will map proximal to ALDH1; GRP78 distal to ITIL and C5; GSN proximal to AK1, ABL, and ASS on HSA 9; GRP78 to MMU 2; and ITIL and GSN to MMU 4.
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PMID:Syntenic conservation between humans and cattle. I. Human chromosome 9. 208 96

We have previously described a patient in whom the breakpoint occurred within the first intron of the BCR gene and have cloned the 9q+ and 22q- junctions. We have now determined the nucleotide sequence around the breakpoints on both translocation products from this patient as well as the corresponding regions from the normal chromosomes 9 and 22. We have compared the sequence with that of the breakpoint regions in the Ph1-positive leukemic patients in order to check for the presence of conserved motifs. A + T-rich sequences and ALU repeat elements are the only sequence characteristics which appear to be very common around translocation regions. The chromosome 9 ABL sequences at or adjacent to the breakpoints present in the 22q- product show homology to the consensus ALU sequence while the chromosome 22 sequences do not, suggesting a non-homologous recombination mechanism. While no sequences are deleted, there is a two-base-pair "homology" at the junction. Therefore, staggered breaks followed by ligation and repair could be part of the mechanism involved in the process of translocation in some cases of Ph1-positive ALL.
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PMID:Characterization of the translocation breakpoint sequences in Philadelphia-positive acute lymphoblastic leukemia. 208 18


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