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)

The proliferation of chronic myelogenous leukemia (CML) cells and the transformation of normal hematopoietic cells by BCR-ABL appear to require the expression of a functional MYC protein, suggesting an approach to treatment of Philadelphia leukemias based on simultaneous targeting of BCR-ABL and c-MYC. To test this hypothesis, CML-blast crisis (CML-BC) primary cells were treated in vitro with bcr-abl and c-myc antisense phosphorothioate oligodeoxynucleotides ([S]ODNs), individually or in combination. Compared with antisense ODNs targeting of individual oncogenes, downregulation of both BCR-ABL and c-MYC by specific antisense [S]ODNs resulted in a synergistic antiproliferative effect. Colony formation of normal bone marrow cells was not affected by either treatment. To assess the therapeutic potential of multiple oncogene downregulation, SCID mice injected with CML-BC primary cells were treated systematically with equal doses of bcr-abl or c-myc antisense [S]ODNs or with a combination of both antisense [S]ODNs. Compared with mice treated with individual compounds, the disease process was significantly retarded in the group treated with both [S]ODNs as revealed by flow cytometry, clonogenic assay, and RT-PCR analysis to detect leukemic cells in mouse tissue cell suspensions. These effects correlated with a markedly increased survival of leukemic mice treated with both antisense [S]ODNs. Leukemic cells harvested from antisense [S]ODN-treated mice were sensitive to the effects of antisense [S]ODNs in vitro, suggesting that the treatment can be successfully repeated. These data demonstrate the therapeutic potential of targeting multiple cooperating oncogenes.
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PMID:Antisense oligodeoxynucleotide combination therapy of primary chronic myelogenous leukemia blast crisis in SCID mice. 870 8

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

The Philadelphia chromosome (Ph) is found in both chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL). The Ph translocation, t(9;22)(q34;q11), can disrupt the BCR gene on chromosome 22 in one to two areas called the major (Mbcr1) and minor (mbcr1) breakpoint cluster regions. In CML the breakpoint has been mapped almost exclusively to Mbcr1, whereas in Ph positive ALL both Mbcr1 and the upstream mbcr1 breakpoints have been described. In this communication we describe an unusual patient with typical chronic phase Ph positive CML and evidence of the uncharacteristic mbcr1 breakpoint, predicting expression of the ALL-type p190 fusion protein. Fluorescence in situ hybridization demonstrated BCR gene rearrangement, the reverse transcription polymerase chain reaction detected the BCR-ABL fusion mRNA characteristic of the mbcr1 breakpoint, and failed to detect BCR-ABL mRNA characteristic of the Mbcr1 breakpoint. Southern blot analysis revealed no rearrangement in Mbcr1, and direct sequencing of the PCR product confirmed it to be the ALL-type mbcr1 fusion mRNA with the first exon of the BCR gene fused to ABL exon a2. This case differs from the previously reported cases of "p190" CML in that the patient presented without abnormal hematopoietic features other than those found in typical CML and provides further evidence that the p190 mRNA is not sufficient to cause an acute rather than chronic leukemia.
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PMID:Unusual expression of mRNA typical of Philadelphia positive acute lymphoblastic leukemia detected in chronic myeloid leukemia. 875 76

A novel variant of the chimeric BCR-ABL mRNA transcript was detected in a patient with Philadelphia chromosome-negative (Ph-) chronic myelogenous leukemia (CML) by multiplex reverse-transcription polymerase chain reaction (RT-PCR). Sequence analysis of the fusion region of the amplified cDNA fragment showed an in-frame joining of exon e6 of the BCR gene and exon a2 of the ABL gene, giving rise to an e6a2 BCR-ABL transcript. This finding was confirmed by Southern blot analysis using a specific probe corresponding to intron 6 of the BCR gene, whereas conventional Southern blot for rearrangement of the major breakpoint cluster region (M-bcr) was negative. Western blot studies detected a BCR-ABL protein slightly larger than p185 BCR-ABL. Metaphase fluorescence in situ hybridization showed an insertion of ABL material into the BCR region without reciprocal BCR translocation. The findings in this case show that atypical BCR-ABL transcripts are detectable even in Ph- CML patients without M-bcr-rearrangements. Multiplex PCR using primers that allow for amplification of all known BCR-ABL transcripts is an appropriate method to exclude these rare variants.
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PMID:A novel BCR-ABL fusion gene (e6a2) in a patient with Philadelphia chromosome-negative chronic myelogenous leukemia. 882 44

Neutrophilic-chronic myeloid leukemia (CML-N) is a rare myeloproliferative disorder that runs a much more benign course than chronic myeloid leukemia, and for which no specific underlying molecular lesion has been described so far. We have analyzed the genomic DNA by Southern blotting and the BCR/ABL hybrid gene transcripts by reverse transcriptase-polymerase chain reaction in three patients with clinical findings of CML-N, who did have a t(9;22) chromosomal translocation. In all patients we have found a rare type of BCR/ABL rearrangement, with a breakpoint between exons c3 and c4 of the BCR gene (corresponding to BCR exons 19 and 20). This was confirmed by hybridization with an oligonucleotide probe spanning the c3/a2 region. This type of junction causes almost the entire BCR gene to fuse with ABL. The junction is in frame and it gives rise to a fusion protein of predicted 230 kD. Our data now provide a molecular diagnostic marker for CML-N, and they are consistent with the notion that the inclusion or exclusion of BCR exons in the fusion protein affects dramatically its capacity to derange myeloid proliferation and differentiation, leading to the appearance of different disease phenotypes.
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PMID:Neutrophilic-chronic myeloid leukemia: a distinct disease with a specific molecular marker (BCR/ABL with C3/A2 junction) 916 72

The human BCR gene encodes a protein with serine/threonine kinase activity and regulatory domains for the small G-proteins RAC and CDC42. Previous work in our laboratory has established that BCR is a substrate for c-FES, a non-receptor tyrosine kinase linked to myeloid growth and differentiation. Tyrosine phosphorylation led to the association of BCR with the RAS guanine nucleotide exchange complex GRB2-SOS in vivo via the GRB2 SH2 domain, linking BCR to RAS signaling (Maru, Y., Peters, K. L., Afar, D. E. H., Shibuya, M., Witte, O. N., and Smithgall, T. E. (1995) Mol. Cell. Biol. 15, 835-842). In the present study, we demonstrate that BCR Tyr-246 and at least one of the closely spaced tyrosine residues, Tyr-279, Tyr-283, and Tyr-289 (3Y cluster), are phosphorylated by FES both in vitro and in 32Pi-labeled cells. Mutagenesis of BCR Tyr-177 to Phe completely abolished FES-induced BCR binding to the GRB2 SH2 domain, identifying Tyr-177 as an additional phosphorylation site for FES. Co-expression of BCR and FES in human 293T cells stimulated the tyrosine autophosphorylation of FES. By contrast, tyrosine phosphorylation of BCR by FES suppressed BCR serine/threonine kinase activity toward the 14-3-3 protein and BCR substrate, BAP-1. These data show that tyrosine phosphorylation by FES affects the interaction of BCR with multiple signaling partners and suggest a general role for BCR in non-receptor protein-tyrosine kinase regulation and signal transduction.
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PMID:Co-expression with BCR induces activation of the FES tyrosine kinase and phosphorylation of specific N-terminal BCR tyrosine residues. 895 35

Fluorescence in situ hybridization (FISH) and the reverse transcription-polymerase chain reaction (RT-PCR) were used to examine a patient presenting with acute myelogenous leukemia (AML) FAB M2, and a complex t(4;9;22)(p14;q34;q11.2). The patient's clinical course was characterized by an aggressive leukemia, resistant to intensive therapy including allogeneic bone marrow transplantation. FISH analysis, using two chromosome painting probes and a BCR/ABL specific probe, confirmed the cytogenetic observation of a 22q11.2-->4p14 and a 4p14-->9q34 exchange, and revealed the presence of a 9q34-->22q11.2, respectively. In addition, RT-PCR demonstrated the presence of a BCR/ABL transcript derived from the major breakpoint cluster region (M-bcr) of the BCR gene. This transcript has been shown to generate an active 210 kDa tyrosine kinase protein more commonly observed in chronic myelogenous leukemia. Because the presentation of AML with this ABL-->BCR fusion product is a rare event, it would seem likely that the additional complex chromosomal rearrangement involving chromosomes 4, 9, and 22 played a role in the aggressive presentation and clinical behavior of this patient's leukemia.
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PMID:Complex chromosome 4, 9, and 22 rearrangement in a patient presenting with AML-FAB M2. 907 96

BCR-ABL is a chimaeric oncogene generated by translocation of sequences from the c-ABL protein-tyrosine kinase gene on chromosome 9 into the BCR gene on chromosome 22. Alternative chimeric proteins, p210(BCR-ABL) and p190(BCR-ABL), are produced that are characteristic of chronic myelogenous leukemia and acute lymphoblastic leukemia, respectively. Their role in the aetiology of human leukemia remains to be defined. We have previously shown that the tumorigenic effect of BCR-ABL oncogenes is mediated by Bcl-2. In addition to Bcl-2, is a protein essential for transformation by BCR-ABL. However, it is not known how Bcl-2 and Ras fit together in cell transformation by BCR-ABL. The data presented here establish that Bcl-2 is a downstream target gene of the Ras signalling pathway in cells transformed by BCR-ABL, and that constitutive Ras activation results in constitutive expression of the gene. Conversely, a truncated form of the BCR-ABL, which lacks a critical BCR region required for activation of the Ras signalling pathway, failed to induce Bcl-2 expression. These results indicate that BCR-ABL prevents apoptosis by inducing Bcl-2 through a signalling pathway involving Ras and links constitutive Ras activation and Bcl-2 gene regulation. Hence, these results further imply that Ras is involved in both mitogenic signals and survival signals.
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PMID:Regulation of Bcl-2 gene expression by BCR-ABL is mediated by Ras. 909 20

Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by the presence of a reciprocal translocation between chromosomes 9 and 22 in at least 95% of cases. At the molecular level, this translocation results in the activation of the ABL oncogene of chromosome 9, which becomes contiguous with the 5' end of the BCR gene on chromosome 22. The breakpoint usually occurs between exons 2 and 3 (b2-a2 rearrangement), or 3 and 4 (b3-12 rearrangement) of the major breakpoint cluster region (M-BCR) of the BCR gene. The aim of the present study was to characterize the type of BCR-ABL transcript in 32 patients with CML using the reverse transcriptase-polymerase chain reaction (RT-PCR) and to determine if this type of rearrangement is related to the survival of the patients. Our results confirmed that RT-PCR is more sensitive than cytogenetic analysis for identifying the Philadelphia (Ph1) chromosome (96.9% vs 79.3%). The frequencies of b2-a2 and b3-a2 rearrangements were 28.1% and 65.7%, respectively. The survival of patients presenting the b2-a2 or the b3-a2 rearrangement was not significantly different (P = 0.27750). The data suggest that the type of transcript has no prognostic value for CML patients.
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PMID:Prognostic significance of BCR-ABL rearrangement in chronic myeloid leukemia. 918 Nov 1

A patient with chronic myeloid leukemia (CML), a normal karyotype and a BCR-ABL rearrangement is presented. Southern blot analysis detected the rearrangement, whereas RT-PCR with b2a2 and b3a2 primers did not. Fluorescence in situ hybridization (FISH) with an ABL probe (9q34.2) and an Mbcr probe (22q11) showed ABL and BCR signals on chromosome 22. Subsequent FISH studies with cosmids mapping to 9q34.3 showed normal hybridization patterns to chromosome 9, suggesting an interstitial insertion of ABL containing DNA sequences into chromosome 22 in this patient. The lack of reciprocal translocation sequences was investigated with RT-PCR, primers a1b and c7. The absence of ABL-BCR gene expression in this and other patients described in the literature with this subtype of Ph-negative CML, does not seem to have an impact on the clinical course of the disease.
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PMID:A Ph-negative chronic myeloid leukemia patient with a non-classical BCR-ABL rearrangement characterized by fluorescence in situ hybridization. 921 26


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