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)

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.
...
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

The presence of BCR-ABL fusion genes has important diagnostic and prognostic implications in chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL). The CML-specific chimeric BCR-ABL gene with a break involving the major breakpoint cluster region (M-bcr) of the BCR-gene has been detected by means of fluorescence in situ hybridization (FISH). In this study, we present a FISH protocol that allows the detection of breaks in both the major and the minor breakpoint cluster region (m-bcr). Three hybridization signals of D107F9, a yeast artificial chromosome (YAC)-derived probe spanning the breakpoint regions of the BCR gene, were indicative of the translocation events. To increase the specificity further, this probe was combined with cos-abl 8, a cosmid probe flanking the breakpoint within the ABL gene for dual-color hybridization. Samples of 21 patients with CML, the ALL-derived cell line SUP-B15, and of seven patients with Philadelphia chromosome (Ph1)-positive ALL (three of them with breakpoints within m-bcr) were examined. BCR-ABL fusion was detected in all cases with high specificity (false-positive nuclei: mean, 0.1%). On cytogenetic preparations, the percentages of BCR-ABL-positive interphase cells ranged from 53% to 91%. Comparable efficiencies were achieved on blood smears. In conclusion, hybridization with D107F9 and cos-abl 8 allows unambiguous diagnosis of BCR-ABL genes and is likely to become an important tool for the monitoring of therapies in patients with CML and ALL.
...
PMID:Detection of chimeric BCR-ABL genes on bone marrow samples and blood smears in chronic myeloid and acute lymphoblastic leukemia by in situ hybridization. 814 58

Chronic myelogenous leukemia (CML) is a myeloproliferative disorder associated with the Philadelphia chromosome (Ph1) in more than 95% of these patients. The Ph1 and the resulting BCR-ABL fused genes are markers for this type of leukemia. In CML, the product of the fused BCR-ABL gene is typically a protein of approximately 2,000 amino acids termed P210 BCR-ABL. We have developed an assay for the BCR-ABL protein involving Western blotting of circulating white blood cells (WBC) with an anti-ABL monoclonal antibody that can detect P210 BCR-ABL and P145 ABL in peripheral blood cells from chronic phase Ph1-positive leukemia patients. This assay was used to analyze the BCR-ABL protein content of circulating WBC from CML patients before and after various treatments. In parallel to changes in percentages of Ph1-positive blood cells as determined by cytogenetic analyses of bone marrow samples, BCR-ABL protein expression in blood cells decreased or increased as patients entered remission or underwent relapse. Of interest, six Ph1-negative CML patients were BCR-ABL protein-positive. All except one had a rearrangement in the major breakpoint cluster region and that patient expressed P185 BCR-ABL and not P210. Our results indicate that the BCR-ABL Western blotting assay has clinical applications for both diagnosis and prospective evaluation of Ph1-positive and Ph1-negative CML patients.
...
PMID:BCR-ABL protein expression in peripheral blood cells of chronic myelogenous leukemia patients undergoing therapy. 820 87

Two-thirds of patients with Philadelphia (Ph) chromosome-positive acute lymphoblastic leukaemia (ALL) have a breakpoint in the minor breakpoint cluster region (m-bcr) of the BCR gene, which results in an e1a2 transcript and a P190BCR-ABL fusion protein. This type of genomic rearrangement occurs very rarely in chronic myeloid leukaemia (CML); it has been reported in only four cases. We describe here a fifth case of P190 CML in which the cytomorphological characteristics were intermediate between CML and chronic myelomonocytic leukaemia (CMML). This case, and the four reported previously, had a consistent and significant monocytosis with a low neutrophil/monocyte ratio in the peripheral blood, resembling CMML. On the other hand, they also had a high percentage of circulating immature granulocytes, basophilia and low neutrophil alkaline phosphatase (NAP) score, which are more commonly found in classical CML. Thus, P190 CML may be a specific form of CML, in which the myeloproliferative process includes the monocytic, as well as the granulocytic lineage. Since the molecular defect in CML is thought to involve a pluripotent stem cell, the different effects of P210BCR-ABL and P190BCR-ABL in CML must reflect the somewhat wider spectrum of activity of the P190BCR-ABL. Other patients with atypical CML or CMML who lack a Ph chromosome may also have an m-bcr breakpoint which would not be detected on standard Southern blots, but which would be detectable by polymerase chain reaction amplification of reverse transcribed RNA.
...
PMID:P190BCR-ABL chronic myeloid leukaemia: the missing link with chronic myelomonocytic leukaemia? 793 80

We performed cytogenetic and molecular analysis of the BCR-ABL rearrangement by polymerase chain reaction (PCR) in 39 consecutive cases of adult acute lymphoblastic leukemia (ALL). Eleven patients had a Philadelphia (Ph) chromosome. Thirteen patients had a BCR-ABL rearrangement, involving minor breakpoint cluster region (m-bcr, situated in intron 1 of the BCR gene) in 11 cases, and major breakpoint cluster region (M-bcr, 'specific' of chronic myeloid leukemia) in the remaining two cases. All of the 12 BCR-ABL cases studied immunologically were of early B, CALLA-positive immunophenotype. The 13 BCR-ABL positive cases included the 11 Ph-positive cases, and two patients with normal karyotype at diagnosis. In the two Ph-negative BCR-positive cases, seven (patient 1) and 18 (patient 2) mitoses had been examined at diagnosis. In patient 1, Ph negativity at diagnosis could certainly be explained by the small number of mitoses analyzed, as a Ph chromosome was found at relapse. This was less probable in patient 2, who raised the issue of whether authentic Ph-negative BCR-ABL-positive ALL exists (as in the chronic myeloid leukemia model) or not. Whatever the explanation, our results suggest that molecular detection of BCR-ABL should be more widely used in B-lineage ALL.
...
PMID:Philadelphia negative, BCR-ABL positive adult acute lymphoblastic leukemia (ALL) in 2 of 39 patients with combined cytogenetic and molecular analysis. 832 Oct 20

The benign phase of chronic myelogenous leukemia (CML) typically is characterized by an overproduction of myeloid cells that eventually progresses to a more acute stage termed blast crisis. This latter stage can exhibit either myeloid or lymphoid blast clones. Our recent results have demonstrated the presence of the P210 BCR-ABL protein in blood cells from benign phase CML patients (Guo et al., Cancer Research 51:3048, 1991). This protein is the product of an 8.5 kb chimeric RNA encoded by fused BCR-ABL genes produced by the formation of the Philadelphia (Ph) chromosome. Using this new assay we have identified a patient with benign-phase CML who produces P190 BCR-ABL, the form of the BCR-ABL protein found in about 50% of cases of acute lymphocytic leukemia (ALL). This patient lacked detectable P210 BCR-ABL protein and did not contain a DNA rearrangement in the major breakpoint cluster region of the BCR gene. Consistent with this result, polymerase chain reaction (PCR) analyses detected a BCR-ABL mRNA with BCR exon 1 fused to ABL exon 2. No BCR-ABL mRNAs with 2'- or 3'-bcr exon to ABL exon 2 fusions were detected in these analyses. Blood cells from this patient lost P190 BCR-ABL after the patient underwent an allogeneic bone marrow transplant, but regained this protein although the patient was still in chronic phase after a subsequent autologous transplant as treatment for graft failure. These findings indicate that P190 BCR-ABL alone is not sufficient to induce a blast crisis phenotype in leukemia patients who are Ph chromosome-positive.
...
PMID:Acute lymphoid leukemia molecular phenotype in a patient with benign-phase chronic myelogenous leukemia. 834 Feb 87

The Philadelphia (Ph) translocation [t(9;22)(q34;q11)] is the most common genetic abnormality in human leukemia; a transposition of the ABL gene to the major-breakpoint cluster region (M-BCR) is associated with the pathogenesis in Ph+ chronic myelogenous leukemia (Ph+ CML) and in some cases of Ph+ acute leukemia (Ph+ AL). Our current understanding of the methylation of human genomes allows us to consider the association between the epigenetic phenomenon and the control of differentiation and proliferation in mammalian cells. In order to determine whether the methylation status of the M-BCR is associated with breakpoint-localization in this region and with the lineage of hematopoietic cells, we have examined 28 patients with Ph+ leukemias, including nine with Ph+ AL, six patients with acute myeloblastic leukemia without Ph (Ph- AML), and five patients with Ph- acute lymphoblastic leukemia (Ph- ALL); using the restriction endonuclease isochizomers, MspI and HpaII. In CML patients in the chronic phase, the hypomethylated status within the normal M-BCR allele is heterogeneous. In contrast, patients with Ph+ CML in the lymphoid blast crisis phase exhibited a 2.5/2.7 kb band with a complete disappearance of the germline M-BCR fragment (type L). This pattern is consistently noted in Ph- ALL cells, and the pattern is quite different from that found in myeloid blast crisis or Ph- AML (type M). In patients with M-BCR-nonrearranged Ph+ ALL, it is suggested that the M-BCR methylation patterns are cell-lineage specific but some Ph+ ALL cells had a hypomethylation pattern that was identical to that observed in Ph- AML, suggesting a distinction of genetic diversity of leukemia cells with the Ph chromosome, especially Ph+ AL.
...
PMID:The methylation status of the major breakpoint cluster region in human leukemia cells, including Philadelphia chromosome-positive cells, is linked to the lineage of hematopoietic cells. 850 75

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.
...
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

A chronic myelogenous leukemia (CML) patient with a masked Ph chromosome due to the translocation (9;10;22)(q34;q24;q11) is reported. Banding analysis showed a 9q+ chromosome typical of standard t(9;22)(q34;q11), and fluorescence in situ hybridization studies confirmed the involvement of a chromosome 10 in the masked Ph formation and also the presence of 3' ABL-DNA sequences in the der(22). This complex rearrangement could be explained by two consecutive translocations: the first, a standard t(9;22) (q34;q11), the second, a translocation between a chromosome 10 and the der(22) with a breakpoint in sequences derived from chromosome 9 telomeric to the ABL gene. By reverse transcription polymerase chain reaction (RT-PCR), we studied the BCR/ABL transcript junction: a chimeric m-RNA b3-a2, indicating a breakpoint within the major breakpoint cluster region, was found.
...
PMID:Fluorescence in situ hybridization provides evidence for two-step rearrangement in a masked Ph chromosome formation. 863 61

Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder of a stem cell, involving myeloid, erythroid, megacaryocyte, lymphoid B-cells and "natural killer" cells. The hallmark of CML is the Philadelphia (Ph) chromosome which is a shortened chromosome 22 (22q-) resulting from a reciprocal translocation involving chromosome 9 and chromosome 22, designed t (9;22) (q34;q11). This translocation juxtaposes parts of two genes; ABL on chromosome 9 and BCR (breakpoint cluster region) on chromosome 22. Transcription of the BCR/ABL fusion gene results in an hybrid mRNA that is translated into a 210 kDa or 190 kDa protein, depending on the location of the breakpoint in the bcr region. This protein plays a key role in CML: its tyrosine-kinase activity, that differs from the normal ABL product, may be involved in leukemic cell growth. Nonetheless, the loss of the negative cell growth regulation by c-ABL, or BCR/ABL fusion protein interaction with other cellular genes (such as RAS or c-MYC) could also be involved in CML pathophysiology. A better understanding of the molecular mecanisms of CML could lead to specific treatment, such as tyrosine-kinase inhibitors, synthetic oligodeoxynucleotides, or site-specific DNA-binding proteins designed against BCR/ABL oncogenic fusion sequence.
...
PMID:[Chronic myeloid leukemia, biological aspects]. 873 43


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

---