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)

To evaluate the remission quality of Philadelphia chromosome (Ph)-positive, BCR/ABL-positive CML patients after allogeneic bone marrow transplantation (BMT) we used the polymerase chain reaction (PCR) to detect BCR-ABL specific RNA in addition to Southern blotting, cytogenetic, and hematological investigation. Fifty-five bone marrow samples of 27 patients in clinical remission were studied by PCR, 0.5 to 99 months (median 8 months) after BMT. The median clinical follow-up of this cohort of patients is 24 months (1-109) after BMT. BCR-ABL transcripts could be detected in 16 out of 27 patients (59%). Risk factors for minimal residual leukemia (MRD) as defined by PCR were the kind of graft-versus-host disease (GvHD) prophylaxis (patients with T-cell-depleted grafts had a higher rate of MRD in comparison to patients treated with methotrexate/cyclosporin A) and the presence or absence of GvHD after BMT (patients without GvHD had a higher incidence of MRD than patients with GvHD). Moreover, the detection of minimal residual leukemia had prognostic significance. Out of 16 patients with minimal residual leukemia as detected by PCR, four patients relapsed clinically and two further cases relapsed cytogenetically. In contrast none of the patients lacking evidence of minimal residual leukemia relapsed. Serial PCR analysis may prove helpful in deciding about further therapeutic interventions (e.g. interferon therapy or adoptive immunotherapy) before leukaemic relapse becomes manifest after BMT.
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PMID:Influence of graft-versus-host disease on the eradication of minimal residual leukemia detected by polymerase chain reaction in chronic myeloid leukemia patients after bone marrow transplantation. 848 29

The 22nd chromosome is known mainly due to chromosome (Philadelphia) which is its derivative-a typical cytogenetic sign of chronic myeloid leukaemia (CML). The molecular genetic finding in these patients is the fused gene which developed by combination of the 3' part of the oncogene ABL from chromosome 9 and 5' part of the gene which developed by combination of the 3' part of the oncogene ABL from chromosome 9 and 5' part of the BCR "gene". The product of the gene retains the original kinase activity (ABL) which is even higher. Detection of BCR/ABL is an important diagnostic aid whic makes it possible to investigate residual diseases in patients after intensive treatment and transplantation of bone marrow and early detection of possible relapses. Among locuses of the 22nd chromosome the author mentions also the locus of the second one of the light immunoglobulin chains-lambda, incl. some of its "related" genes, the group of crystalline locuses (CRYB), the locus of the beta-chain of the GM-CSF receptor, the myoglobin locus (MB) and finally locus NF2 of central neurofibromatosis-bilateral neurinoma of the acoustic nerve.
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PMID:[The human genome--chromosome 22]. 859 11

The BCR/ABL fusion gene in 31 patients with chronic myeloid leukemia (CML) was detected by RT/PCR. In 18 cases of Ph' positive patients, 13 had BCR 3/ABL II rearrangement, 1 had BCR 2/ABL II rearrangement and 4 had both rearrangements. One case with complex translocation: 46,XY,t(9;9;22), had BCR 3/ABL II rearrangement. In 8 cases of Ph' negative patients, 4 had BCR 3/ABL II rearrangement, 3 had both rearrangements while 1 had no BCR/ABL rearrangement. Interestingly, in 4 patients who had no cytogenetic result, we could observe BCR 3/ABL II rearrangement in 3 cases and both rearrangements in 1 case. The results suggest that this procedure is sensitive and independent of the presence or absence of an identifiable Ph' chromosome.
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PMID:Detection of BCR/ABL fusion gene in CML: a preliminary report. 862 6

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.
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PMID:Fluorescence in situ hybridization provides evidence for two-step rearrangement in a masked Ph chromosome formation. 863 61

Chronic myelogenous leukemia (CML) and some acute lymphoblastic leukemias (ALL) are caused by the t(9;22) chromosome translocation, which produces the constitutively activated BCR/ABL tyrosine kinase. When introduced into factor dependent hematopoietic cell lines, BCR/ABL induces the tyrosine phosphorylation of many cellular proteins. One prominent BCR/ABL substrate is p120CBL, the cellular homolog of the v-Cbl oncoprotein. In an effort to understand the possible contribution of p120CBL to transformation by BCR/ABL, we looked for cellular proteins which associate with p120CBL in hematopoietic cell lines transformed by BCR/ABL. In addition to p210BCR/ABL and c-ABL, p120CBL coprecipitated with an 85 kDa phosphoprotein, which was identified as the p85 subunit of PI3K. Anti-p120CBL immunoprecipitates from BCR/ABL-transformed, but not from untransformed, cell lines contained PI3K lipid kinase activity. Interestingly, the adaptor proteins CRKL and c-CRK were also found in these complexes. In vitro binding studies indicated that the SH2 domains of CRKL and c-CRK bound directly to p120CBL, while the SH3 domains of c-CRK and CRKL bound to BCR/ABL and c-ABL. The N-terminal and the C-terminal SH2 and the SH3 domain of p85PI3K bound directly in vitro to p120CBL. The ABL-SH2, but not ABL-SH3, could also bind to p120CBL. These data suggest that BCR/ABL may induce the formation of multimeric complexes of signaling proteins which include p120CBL, PI3K, c-CRK or CRKL, c-ABL and BCR/ABL itself.
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PMID:The proto-oncogene product p120CBL and the adaptor proteins CRKL and c-CRK link c-ABL, p190BCR/ABL and p210BCR/ABL to the phosphatidylinositol-3' kinase pathway. 863 6

Fluorescence in situ hybridization (FISH) and cytogenetic analysis were carried out in 33 transplanted patients suffering from different hematologic disease using probes for X and Y chromosomes and ABL and BCR genes. FISH showed that recipient cells were invariably present during post-transplant follow-up. Stable minimal residual disease was associated with clinical and hematologic remission, while a progressive increase of host cells was strictly related with disease relapse. Cytogenetic investigation on the same samples showed recipient cells only in few cases. It was concluded that FISH analysis is useful for: (1) characterizing cases in which standard cytogenetic analysis has failed; (2) detecting host cells in sex-mismatched transplanted patients; and (3) evaluating Ph-negative CML with the BCR/ABL rearrangement. The possibility of detecting chromosome rearrangements in interphase nuclei using FISH analysis improves diagnosis and prediction of disease evolution and prompts earlier therapeutic approaches.
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PMID:FISH detection of mixed chimerism in 33 patients submitted to bone marrow transplantation. 864 Jan 72

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.
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PMID:[Chronic myeloid leukemia, biological aspects]. 873 43

A variant form of BCR/ABL junction was identified in a patient with chronic myelogenous leukaemia (CML). The BCR/ABL fusion mRNA of this patient showed in-frame junction between BCR exon c3 and ABL exon 2. Although the diagnosis of CML was made, the patient showed clinical features of essential thrombocythaemia (ET) rather than that of typical CML. Treatment with interferon-alpha showed no cytogenetic response. The c3-a2 type of BCR/ABL junction seems to be associated with elevated platelet count and thus could form a novel clinical entity different from typical CML.
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PMID:Elevated platelet count features the variant type of BCR/ABL junction in chronic myelogenous leukaemia. 875 98

The Philadelphia chromosome translocation generates a chimeric oncogene, BCR/ABL which causes chronic myelogenous leukemia. Two different fusion proteins can be produced, p190BCR/ABL and p210BCR/ABL, depending on the location of the breakpoint in BCR. Although the ABL tyrosine kinase activity of the resulting oncoprotein is essential for transformation, the exact functional contribution of BCR to transformation is unclear. A novel oncogene containing ABL is formed by the (9;12) translocation which fuses part of the ets-family member TEL to c-ABL in patients with acute leukemia. In an effort to compare the biological effects of various ABL oncogenes, we transformed two different factor-dependent murine hematopoietic cell lines with cDNA's encoding p210BCR/ABL, p190BCR/ABL, or TEL/ABL. Transfection of each of the three activated ABL oncogenes resulted in rapid emergence of growth factor-independence, and 2-4 sublines from each cell line with each oncogene were further studied. Each oncogene induced an increase in the tyrosine phosphorylation of cellular proteins and autophosphorylation of the oncoprotein itself. Overall, the pattern of increased tyrosine phosphorylation was similar in the cell lines, suggesting that many of the major substrates were identical. We specifically examined a series of proteins known to be p210BCR/ABL substrates, including rasGAP, Shc, SH-PTP2, SH-PTP1, CRK-L, CBL, paxillin, and STATs, and found that each were also tyrosine phosphorylated in response to p190BCR/ABL and TEL/ABL. These results suggest that the function of BCR can be largely replaced by the unrelated protein TEL with regards to transformation of murine hematopoietic cell lines to factor-independence, and support the hypothesis that a major contribution of both fusion partners is to activate the ABL tyrosine kinase.
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PMID:p210BCR/ABL, p190BCR/ABL, and TEL/ABL activate similar signal transduction pathways in hematopoietic cell lines. 880 88

The Philadelphia chromosome (Ph) translocation generates a chimeric tyrosine kinase oncogene, BCR/ABL, which causes chronic myelogenous leukemia (CML) and a type of acute lymphoblastic leukemia (ALL). In primary samples from virtually all patients with CML or Ph+ALL, the CRKL adapter protein is tyrosine phosphorylated and physically associated with p210(BCR/ABL). CRKL has one SH2 domain and two SH3 domains and is structurally related to c-CRK-II (CRK) and the v-Crk oncoprotein. We have previously shown that CRKL, but not the related adapter protein c-CRK, is tyrosine phosphorylated in cell lines transformed by BCR/ABL, and that CRKL binds to BCR/ABL through the CRKL-SH3 domains. Furthermore, the CRKL-SH2 domain has been shown to bind one or more cellular proteins, one of which is p120(CBL). Here we demonstrate that another cellular protein linked to BCR/ABL through the CRKL-SH2 domain is p130(CAS). p130(CAS) was found to be tyrosine phosphorylated and associated with CRKL in BCR/ABL expressing cell lines and in samples obtained from CML and ALL patients, but not in samples from controls. In both normal and BCR/ABL transformed cells, p130(CAS) was detected in focal adhesion-like structures, as was BCR/ABL. In normal cells, the focal adhesion proteins tensin, p125(FAK), and paxillin constitutively associated with p130(CAS). However, in BCR/ABL transformed cells, the interaction between p130(CAS) and tensin was disrupted, while the associations between p130(CAS), p125(FAK), and paxillin were unaffected. These results suggest that the BCR/ABL oncogene could alter the function of p130(CAS) in at least three ways: tyrosine phosphorylation, inducing constitutive binding of CRKL to a domain in p130(CAS) containing Tyr-X-X-Pro motifs (substrate domain), and disrupting the normal interaction of p130(CAS) with the focal adhesion protein tensin. These alterations in the structure of signaling proteins in focal adhesion like structures could contribute to the known adhesion abnormalities in CML cells.
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PMID:p130CAS forms a signaling complex with the adapter protein CRKL in hematopoietic cells transformed by the BCR/ABL oncogene. 881 Feb 78


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