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

---

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

We performed molecular studies to resolve the status of BCR and ABL in the bone marrow cells of a CML patient with a Ph chromosome resulting from a complex translocation involving chromosomes 9, 15, and 22. DNA digestion with BamHI, HindIII, and BglII, followed by hybridization to a bcr-specific 32P-labeled probe, showed a rearranged banding pattern confirming the involvement of the bcr locus in the translocation. Furthermore, total cellular RNA isolated from the marrow was subjected to reverse transcription into cDNA and amplified by PCR with primers specific for BCR-ABL fusion cDNA. The amplified products obtained from this patient and from a CML patient with the standard t(9;22) were both of the expected length of approximately 317 bp.
...
PMID:Molecular confirmation of BCR-ABL fusion in a chronic myeloid leukemia with a complex translocation involving chromosomes 9, 15, and 22. 137 43

The Philadelphia (Ph1) chromosome, or its molecular counterpart, the BCR-ABL fusion gene, is a rare but important prognostic indicator in childhood acute lymphoblastic leukemia (ALL), but its impact on adult ALL has not been well ascertained. A prospective study of the BCR-ABL fusion gene was begun on patients entered on clinical trials conducted by the Cancer and Leukemia Group B (CALGB). All patients received intensive, multiagent chemotherapy that included daunorubicin. Over 2 years, 56 patients were studied for molecular evidence of a BCR-ABL gene using Southern blot and pulsed-field gel hybridization analysis. Results were compared with cytogenetic detection of a Ph1 chromosome, and clinical features were compared for the BCR-ABL-positive and -negative groups. Molecular methods detected the BCR-ABL gene in 30% of cases compared with cytogenetic detection of the Ph1 chromosome in only 23%. The majority of cases (76%) showed the p190 gene subtype similar to pediatric ALL; the BCR-ABL-positive cases displayed a more homogeneous immunophenotype than the BCR-ABL-negative cases and were predominantly CALLA positive (86%) and B-cell surface antigen positive (82%). The rate of achieving complete remission was similar in the BCR-ABL-positive and -negative groups (71% and 77%, respectively, P = .72). There were more early relapses in the BCR-ABL-positive group, resulting in a shorter remission duration that was especially marked in the CALLA-positive and B-cell antigen-positive populations. These preliminary data suggest that the impact of the BCR-ABL gene on clinical outcome in ALL may be on maintenance of complete remission (CR) rather than achievement of CR when aggressive, multiagent chemotherapy is used. This study identifies the BCR-ABL gene as an important factor in adult ALL and demonstrates the utility of molecular methods for its accurate diagnosis.
...
PMID:Clinical significance of the BCR-ABL fusion gene in adult acute lymphoblastic leukemia: a Cancer and Leukemia Group B Study (8762). 146 14

The Philadelphia chromosome (Ph1) was the first genetic change to be associated consistently with leukemia, and it is one of the best understood on the molecular level. Because of this, it is an excellent model to investigate the application of molecular techniques to the clinical setting. These techniques are reviewed as are their clinical use in chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL), and transplantation. The Ph1 is caused by the fusion of two genes on chromosomes 9 and 22, resulting in the BCR-ABL fusion gene. This new gene is believed to be the cause of these Ph1-positive leukemias. The ability to detect the BCR-ABL fusion gene evolved from cytogenetic detection to Southern blot analysis, and now includes sophisticated techniques such as polymerase chain reaction (PCR) methods and pulsed-field gels. Diagnosis of the BCR-ABL fusion gene by Southern blot detection of bcr genetic rearrangements is the prototype of molecular cancer diagnosis. The sensitivity and clinical uses of this test are reviewed, especially its application to monitoring the response to treatment. PCR methods enable the researcher to detect 1 CML cell in a population of 10(5) cells. Clinical experience with PCR, especially in transplantation medicine, is providing a better understanding of the meaning of the terms "remission" and "cure." Newer techniques using fluorescent in situ hybridization have considerable potential for BCR-ABL detection, but no clinical experience has been gained with these techniques currently. The diagnosis of the BCR-ABL fusion gene in ALL has important clinical implications because it is the most common molecular genetic change in adult ALL and is associated with short remissions and poor outcome in all age groups. Diagnosis of the BCR-ABL fusion in ALL is difficult because the molecular findings are more heterogeneous than they are in CML. The methods available and their accuracy and sensitivity are compared. A review of their clinical impact is included.
...
PMID:The role of molecular techniques in the clinical management of leukemia. Lessons from the Philadelphia chromosome. 151 23

Joining of the BCR and ABL genes is an essential feature of the group of human leukemias characterized by the Philadelphia chromosome and there is recent evidence that the human BCR-ABL fusion gene induces leukemia in experimental animals. Joining of these two genes is the result of cytogenetic translocation, usually the t(9;22)(q34;q11), but sometimes of more complex translocations involving one or more chromosomes in addition to chromosomes 9 and 22. The leukemic cells of some patients carry the BCR-ABL fusion gene but have an apparently normal karyotype. Recent studies show that these cells conceal complex chromosome rearrangements. Because the BCR-ABL fusion gene appears to be the result of cytogenetic rearrangement in all cases of these leukemias, the causes and mechanism of chromosome rearrangement will be relevant to the development of leukemia in man. We examine mechanisms of chromosome rearrangement and propose that both simple and complex chromosome translocations result from a single, though sometimes complex, interchange event.
...
PMID:Complex chromosomal translocations in the Philadelphia chromosome leukemias. Serial translocations or a concerted genomic rearrangement? 175 91

Leukemic cells from a patient with Ph-negative chronic myeloid leukemia (CML) had a normal karyotype. M-BCR was rearranged and chromosome in situ hybridization showed an ABL insertion between 5' and 3' M-BCR on an apparently normal chromosome 22. The association of 5' BCR and 3' ABL at the 5' junction of the chromosome 9 insert was typical of that found for the BCR-ABL fusion gene in other patients with the standard t(9;22) and CML. With an M-bcr-3' probe, we cloned and characterized a 3' junction fragment. Field inversion gel electrophoresis and chromosome in situ hybridization studies using a probe isolated from genomic DNA 5' of the junction showed that 3' M-BCR was joined to a region of chromosome 9q34 rich in repetitive sequences and lying some distance 3' of ABL. The chromosome 9 insert was at least 329 kilobases long and included 3' ABL and a larger portion of chromosome 9q34. Our results allowed us to exclude transposon- or retroviral-mediated insertion of ABL into chromosome 22. Instead, we favored a two-translocation model in which a second translocation reconstituted a standard t(9;22)(q34;q11) but left the chromosome 9 insert, including 3' ABL, in chromosome 22.
...
PMID:Ph-negative chronic myeloid leukemia: molecular analysis of ABL insertion into M-BCR on chromosome 22. 217 2

The Philadelphia (Ph1) chromosome results in a fusion of portions of the BCR gene from chromosome 22 and the ABL gene from chromosome 9, producing a chimeric BCR-ABL mRNA and protein. In lymphoblastic leukemias, there are two molecular subtypes of the Ph1 chromosome, one with a rearrangement of the breakpoint cluster region (bcr) of the BCR gene, producing the same 8.5-kilobase BCR-ABL fusion mRNA seen in chronic myelogenous leukemia (CML), and the other, without a bcr rearrangement, producing a 7.0-kilobase BCR-ABL fusion mRNA that is seen only in acute lymphoblastic leukemia (ALL). We studied the molecular subtype of the Ph1 chromosome in 11 cases of Ph1-positive ALL, including 2 with a previous diagnosis of CML, using a sensitive method to analyze the mRNA species based on the polymerase chain reaction (PCR). We observed unexpected heterogeneity in BCR-ABL mRNA in this population; in particular, 1 of 6 bcr-rearranged cases and 1 of 5 bcr-unrearranged cases contained none of the known fusion mRNA species, while 1 of the bcr-rearranged cases contained both. This latter case is particularly interesting because it suggests that the acquisition of an additional BCR-ABL fusion species may be a mechanism of disease progression. We conclude that the PCR gives additional information about the Ph1 chromosome gene products that cannot be obtained by genomic analysis, but that it cannot be used as the sole means of detection of this chromosomal abnormality in ALL because of the high incidence of false negative results.
...
PMID:Unexpected heterogeneity of BCR-ABL fusion mRNA detected by polymerase chain reaction in Philadelphia chromosome-positive acute lymphoblastic leukemia. 249 81

Philadelphia chromosome-positive acute lymphoblastic leukemia occurs in two molecular forms, those with and those without rearrangement of the breakpoint cluster region on chromosome 22. The molecular abnormality in the former group is similar to that found in chronic myelogenous leukemia. To characterize the abnormality in the breakpoint cluster region-unrearranged form, we have mapped a 9;22 translocation from the Philadelphia chromosome-positive acute lymphoblastic leukemia cell line SUP-B13 by using pulsed-field gel electrophoresis and have cloned the DNA at the translocation junctions. We demonstrate a BCR-ABL fusion gene on the Philadelphia chromosome. The breakpoint on chromosome 9 is within ABL between exons Ia and II, and the breakpoint on chromosome 22 is approximately equal to 50 kilobases upstream of a breakpoint cluster region in an intron of the BCR gene. This upstream BCR breakpoint leads to inclusion of fewer BCR sequences in the fusion gene, compared with the BCR-ABL fusion gene of chronic myelogenous leukemia. Consequently, the associated mRNA and protein are smaller. The exons from ABL are the same. Analysis of leukemic cells from four other patients with breakpoint cluster region-unrearranged Philadelphia chromosome-positive acute lymphoblastic leukemia revealed a rearrangement on chromosome 22 close to the breakpoint in SUP-B13 in only one patient. These data indicate that breakpoints do not cluster tightly in this region but are scattered, possibly in a large intron. Given the large size of BCR and the heterogeneity in breakpoint location, detection of BCR rearrangement by standard Southern blot analysis is difficult. Pulsed-field gel electrophoresis should allow detection at the DNA level in every patient and thus will permit clinical correlation of the breakpoint location with prognosis.
...
PMID:Heterogeneity of genomic fusion of BCR and ABL in Philadelphia chromosome-positive acute lymphoblastic leukemia. 283 55

The ABL proto-oncogene on the Philadelphia chromosome is 'activated' by its translocation in a manner similar to its activation by the murine Abelson leukemia virus--with the formation of a fusion protein with a new N-terminus and enhanced tyrosine kinase activity. Study of this BCR-ABL fusion gene has led to the development of molecular probes which are beginning to play an important role in the diagnosis and clinical management of chronic myelogenous leukemia, and may ultimately lead to better understanding of the biology of the disease. The role of ABL on the Philadelphia chromosome in acute lymphoblastic leukemia is only now beginning to be understood, but is likely to be similar, and a new ABL species has already been identified by several groups. It is likely that this protein is the product of a fusion gene, as it is in chronic myelogenous leukemia, but definitive proof awaits molecular cloning of the translocation breakpoint. Aside from its activation by the Ph1 chromosome, ABL has not been found to have a role in any other human cancer.
...
PMID:The ABL oncogene in human leukemias. 328 49

The Philadelphia chromosome (Ph1) is a translocation between chromosomes 9 and 22 that is found in chronic myelogenous leukemia (CML) and a subset of acute lymphocytic leukemia patients (ALL). In CML, this results in the expression of a chimeric 8.5-kilobase BCR-ABL transcript that encodes the P210BCR-ABL tyrosine kinase. The Ph1 chromosome in ALL expresses a distinct ABL-derived 7-kilobase messenger RNA that encodes the P185ALL-ABL protein. Since the expression of different oncogene products may play a role in the distinctive presentation of Ph1-positive ALL versus CML, it is necessary to understand the molecular basis for the expression of P185ALL-ABL. Both P210BCR-ABL and P185ALL-ABL are recognized by an antiserum directed to BCR determinants in the amino-terminal region of both proteins. Antisera to BCR determinants proximal to the BCR-ABL junction in CML immunoprecipitated P210BCR-ABL but not P185ALL-ABL. Nucleotide sequence analysis of complementary DNA clones made from RNA from the Ph1-positive ALL SUP-B15 cell line, and S1 nuclease protection analysis confirmed the presence of BCR-ABL chimeric transcripts in Ph1-positive ALL cells. In Ph1-positive ALL, ABL sequences were joined to BCR sequences approximately 1.5 kilobases 5' of the CML junction. P185ALL-ABL represents the product of a BCR-ABL fusion gene in Ph1-positive ALL that is distinct from the BCR-ABL fusion gene of CML.
...
PMID:Expression of a distinctive BCR-ABL oncogene in Ph1-positive acute lymphocytic leukemia (ALL). 342 16

Leukemic cells from two patients with Philadelphia-negative chronic myeloid leukemia (CML) were investigated: 1) Cytogenetics showed a normal 46,XY karyotype in both cases, 2) molecular studies revealed rearrangement of the M-BCR region and formation of BCR-ABL fusion mRNA with b2a2 (patient 1) or b3a2 (patient 2) configuration, and 3) fluorescence in situ hybridization (FISH) demonstrated relocation of the 5' BCR sequences from one chromosome 22 to one chromosome 9. The ABL probe hybridized to both chromosomes 9 at band q34, while two other probes which map centromeric and telomeric of BCR on 22q11 hybridized solely with chromosome 22. For the first time, a BCR-ABL rearrangement is shown to take place on 9q34 instead of in the usual location on 22q11. A rearrangement in the latter site is found in all Ph-positive CML and in almost all investigated CML with variant Ph or Ph-negative, BCR-positive cases. The few aberrant chromosomal localizations of BCR-ABL recombinant genes found previously were apparently the result of complex and successive changes. Furthermore in patient 2, both chromosomes 9 showed positive FISH signals with both ABL and BCR probes. Restriction fragment length polymorphism (RFLP) analysis indicated that mitotic recombination had occurred on the long arm of chromosome 9 and that the rearranged chromosome 9 was of paternal origin. The leukemic cells of this patient showed a duplication of the BCR-ABL gene, analogous to duplication of the Ph chromosome in classic CML. In addition they had lost the maternal alleles of the 9q34 chromosomal region.(ABSTRACT TRUNCATED AT 250 WORDS)
...
PMID:Translocation of BCR to chromosome 9: a new cytogenetic variant detected by FISH in two Ph-negative, BCR-positive patients with chronic myeloid leukemia. 751 67


1 2 3 4 5 6 7 8 9 10 Next >>

---