Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fluorescence in situ hybridization (FISH) technique has been successfully used to detect the BCR-ABL gene fusion in chronic myeloid leukemia (CML) with the classic form of the Philadelphia chromosome (Ph). We applied FISH to study three CML patients showing variant Ph chromosome (either complex or simple type). The results demonstrate that the use of a yeast artificial chromosome (YAC)-derived probe (D107F9) and a cosmid probe (cos-abl 8), specific for BCR and ABL genes respectively, allows also the detection of the BCR-ABL fusion in CML patients with variant Ph.
 ...
PMID:Detection of the breakpoint cluster region-ABL fusion in chronic myeloid leukemia with variant Philadelphia chromosome translocations by in situ hybridization. 869 23

Cryptic t(12;21)(p12-13;q22) leading to TEL-AML1 fusion has recently been recognized as the most frequent genetic rearrangement in childhood acute lymphoblastic leukemia (ALL) in Western countries. More recently, we found a similar frequency of this abnormality in Chinese children with ALL in Taiwan. In this study, we assessed further the frequency of TEL-AML1 fusion as well as that of BCR-ABL in Chinese adults with ALL, using reverse transcriptase-polymerase chain reaction assays. Among the 81 cases with newly diagnosed B lineage ALL studied, none had the TEL-AML1 fusion whereas 30 had the BCR-ABL fusion. The lack of cases with the TEL-AML1 fusion together with the high frequency of BCR-ABL fusion could largely account for the poorer outcome of adult ALL as compared with childhood ALL.
 ...
PMID:Lack of TEL-AML1 fusion transcript resulting from a cryptic t(12;21) in adult B lineage acute lymphoblastic leukemia in Taiwan. 875 62

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.
 ...
PMID:Unusual expression of mRNA typical of Philadelphia positive acute lymphoblastic leukemia detected in chronic myeloid leukemia. 875 76

In chronic myeloid leukemia (CML) the classical 9;22 translocation results in a BCR-ABL fusion gene, which encodes chimeric BCR-ABL fusion 210 kD oncoproteins (p210BCR-ABL). The two main p210BCR-ABL fusion variants in CML, b2a2 and b3a2 are examples of well characterized antigens expressed by malignant cells. The possibility of an immunotherapeutic approach involving the fusion part of p210BCR-ABL in CML has previously been illustrated by observed peptide binding to major histocompatibility complex (MHC) class I alleles and by demonstrating the immunogenicity of p210BCR-ABL breakpoint peptides. In this report we show that in vitro immunization of human T cells with a 17 amino acid (aa) peptide representing the p210BCR-ABL fusion region resulted in peptide specific CD4+ T-cell lines designated P4, P6, and P7. HLA DR4 (DRB1*0401) restricted T-cell line P4 and several subsequently derived clones recognized HLA-DRB1*0401 and p210b3a2-mRNA expressing blasts from an allogeneic patient with CML in blast crisis. Recognition appeared DR expression-dependent. No responses were observed with DR4 positive p210BCR-ABL negative cells or with p210b3a2 leukemic cells with absent or insufficient expression of DR4. These observations indicate that oncoprotein p210b3a2 can be degraded and processed for presentation by MHC class II molecules at the surface of leukemic cells. The BCR-ABL fusion region is in all likelihood presented as peptides by HLA DR and thus capable to act as a distinctive tumor antigen to peptide specific CD4+ T cells.
 ...
PMID:Recognition of BCR-ABL positive leukemic blasts by human CD4+ T cells elicited by primary in vitro immunization with a BCR-ABL breakpoint peptide. 889 19

The tyrosine kinase activity of BCR-ABL fusion proteins plays an important role in the pathogenesis of leukemia that is for the Philadelphia chromosome (Ph1). Because nuclear c-ABL is regulated during the cell cycle through a specific interaction with the retinoblastoma protein (pRB), the possible interaction of BCR-ABL with pRB in Ph1-positive cell lines was investigated. P145 c-ABL as well as P190 and P210 BCR-ABL proteins interacted with pRB. Furthermore, c-ABL and BCR-ABL associated with both phosphorylated and nonphosphorylated forms of pRB. These findings suggest that BCR-ABL interferes with pRB function and thereby regulates cell growth.
 ...
PMID:Interaction of BCR-ABL with the retinoblastoma protein in Philadelphia chromosome-positive cell lines. 907 15

BCR-ABL fluorescence in situ hybridization has a useful role to play in experimental and clinical investigations of chronic myeloid leukaemia. However, the interpretation of results is complicated by variability in the false positive rate (FPR) and false negative rate (FNR). We therefore examined the effects on FNR and FPR of three factors, namely, the criteria used for defining a fusion signal, nucleus size, and the genomic position of the ABL breakpoint. We established two different criteria for BCR-ABL positivity: by criterion A cells were scored as positive when BCR and ABL signals were overlapping or touching and by criterion B cells were positive if they satisfied criterion A or if the signals were separated by up to one signal diameter. We measured nucleus size and Philadelphia (Ph) positivity in 573 cells from normal persons and 787 cells from the Ph+ SD-1 cell line and related results to FNRs and FPRs. We also assessed the FNR in Ph+ CFU-GM colonies from five patients with different ABL breakpoints. We showed that each of these factors influenced the FNR and FPR. The less strict criterion (B) for Ph positivity increased the FPR but reduced the FNR, the FPR increased as the nucleus size decreased, and the FNR was greatest in CML cells with a 5' ABL breakpoint. We conclude that these factors should be considered when evaluating the results of FISH studies to detect the BCR-ABL fusion gene and that analogous factors may influence results of FISH studies directed at other fusion genes.
 ...
PMID:Factors influencing the false positive and negative rates of BCR-ABL fluorescence in situ hybridization. 908 64

We present a patient who underwent sibling allogeneic BMT because of refractory Ph+ve ALL and remained BCR-ABL-positive after marrow grafting. Haemopoietic precursor cells were predominantly BCR-ABL-negative and of donor origin. In T cells an exclusively donor genotype was demonstrated. Despite donor leucocyte infusion (DLI), 20 weeks after BMT BCR-ABL fusion mRNA increased in semiquantitative polymerase chain reaction and leukaemic infiltration of the patient's bone marrow was seen. After a second course of DLI the patient achieved sustained molecular remission but he developed severe graft-versus-host disease (GvHD) and died from bacterial sepsis 9 months after DLI.
 ...
PMID:Relapse of Philadelphia chromosome positive acute lymphoblastic leukaemia after marrow transplantation: sustained molecular remission after early and dose-escalating infusion of donor leucocytes. 913 59

The Philadelphia chromosome, detected in virtually all cases of chronic myelogenous leukemia (CML), is formed by a reciprocal translocation between chromosomes 9 and 22 that fuses BCR-encoded sequences upstream of exon 2 of c-ABL. The BCR-ABL fusion creates a gene whose protein product, p210BCR-ABL, has been implicated as the cause of the disease. Although ABL kinase activity has been shown to be required for the transforming abilities of BCR-ABL and numerous substrates of the BCR-ABL tyrosine kinase have been identified, the requirement of most of these substrates for the transforming function of BCR-ABL is unknown. In this study we mapped a direct binding site of the c-CBL proto-oncogene to the SH2 domain of BCR-ABL. This interaction only occurs under conditions where c-CBL is tyrosine-phosphorylated. Despite the direct interaction of c-CBL with the SH2 domain of BCR-ABL, deletion of the SH2 domain of BCR-ABL did not result in an alteration in the complex formation of BCR-ABL and c-CBL, suggesting that another site of direct interaction between c-CBL and BCR-ABL exists or that another protein mediates an indirect interaction of c-CBL and BCR-ABL. Since CRKL, an SH2, SH3 domain-containing adapter protein is known to bind directly to BCR-ABL and also binds to tyrosine-phosphorylated c-CBL, the ability of CRKL to mediate a complex between c-CBL and BCR-ABL was examined.
 ...
PMID:Interactions of CBL with BCR-ABL and CRKL in BCR-ABL-transformed myeloid cells. 919 15

With the eventual goal of developing a treatment for chronic myelogenous leukemia (CML), attempts have been made to design hammerhead ribozymes that can specifically cleave BCR-ABL fusion mRNA. In the case of L6 BCR-ABL fusion mRNA (b2a2 type; BCR exon 2 is fused to ABL exon 2), which has no effective cleavage sites for conventional hammerhead ribozymes near the BCR-ABL junction, it has proved very difficult to cleave the chimeric mRNA specifically. Several hammerhead ribozymes with relatively long junction-recognition sequences have poor substrate-specificity. Therefore, we explored the possibility of using newly selected DNA enzymes that can cleave RNA molecules with high activity to cleave L6 BCR-ABL fusion (b2a2) mRNA. In contrast to the results with the conventional ribozymes, the newly designed DNA enzymes, having higher flexibility for selection of cleavage sites, were able to cleave this chimeric RNA molecule specifically at sites close to the junction. Cleavage occurred only within the abnormal BCR-ABL mRNA, without any cleavage of the normal ABL or BCR mRNA. Thus, these chemically synthesized DNA enzymes seem to be potentially useful for application in vivo , especially for the treatment of CML, if we can develop exogenous delivery strategies.
 ...
PMID:Comparison of the specificities and catalytic activities of hammerhead ribozymes and DNA enzymes with respect to the cleavage of BCR-ABL chimeric L6 (b2a2) mRNA. 922 7

We used reverse transcriptase polymerase chain reaction (RT-PCR) assays to examine primary leukemic cells in on-study diagnostic bone marrow specimens from 642 children with newly diagnosed acute lymphoblastic leukemia (ALL) for the expression of MLL-AF4, E2A-PBX1, and BCR-ABL fusion transcripts. All PCR assays were performed centrally in the Children's Cancer Group ALL Biology Reference Laboratory. MLL-AF4 transcript was found in only 0.7% of the study population which excluded infants. E2A-PBX1 transcript was found in 2.5% of the study population and 3.3% of B-precursor cases. Expression was associated with massive hepatomegaly. BCR-ABL transcript was found in 2.3% of cases and correlated with older age, induction failure, and inferior event-free survival (EFS). RT-PCR assays allow rapid identification of patients with MLL-AF4 and BCR-ABL positive ALL. These patients have a poor outcome with contemporary therapy and rapid identification facilitates timely allocation to innovative treatment programs.
 ...
PMID:Expression of BCR-ABL, E2A-PBX1, and MLL-AF4 fusion transcripts in newly diagnosed children with acute lymphoblastic leukemia: a Children's Cancer Group initiative. 925 Jul 88


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