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)

Chronic myeloid leukaemia (CML) is caused by the product of the BCR-ABL oncogene, located on the Philadelphia (Ph) chromosome. BCR-ABL is generated as a result of a reciprocal t(9;22) chromosomal translocation. The mechanisms responsible for this illegitimate recombination event remain elusive but are presumed to require a close spatial association of the translocation partners (chromosomes 9 and 22). BCR-ABL fusion transcripts can be detected by a sensitive reverse transcription-polymerase chain reaction (RT-PCR) in the leucocytes of some healthy individuals suggesting that chromosomal translocations may occur frequently in the general population. The presence of BCR-ABL fusion transcripts does not imply that the individual will inevitably develop CML since other conditions must be favourable for expansion of the abnormal clone. Breakpoints in the ABL gene occur within a 5' segment. BCR-ABL fusion transcripts lack ABL exon a1 and consist of BCR exons fused directly to ABL exon a2. The breakpoints in the BCR gene on chromosome 22 are found within three defined regions. Depending on the position of the BCR breakpoint, fusion genes are generated that encode 190-, 210- or 230-kD forms of the Bcr-Abl tyrosine kinase. Since the ABL component of the fusion gene is largely invariant, it follows that variability in disease phenotype may be due to protein sequences encoded by the translocation partner, BCR. Different disease phenotypes are associated with each of the three Bcr-Abl oncoproteins, p190(Bcr-Abl), p210(Bcr-Abl )and p230(Bcr-Abl). Mechanisms associated with malignant transformation include altered cellular adhesion, activation of mitogenic signalling pathways, inhibition of apoptosis and proteasomal degradation of physiologically important cellular proteins. CML is subject to an inexorable progression from an 'indolent' chronic phase to a terminal blast crisis. Disease progression is presumed to be associated with the phenomenon of genomic instability.
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PMID:Cytogenetic and molecular genetic aspects of chronic myeloid leukaemia. 1243 15

The aim of this study was to enhance the antileukemic efficacy of the alkylphosphocholine erucylphospho-N,N,N-trimethylpropylammonium (ErPC3) in chronic myeloid leukemia (CML)-derived cell lines by a bcr-directed antisense oligonucleotide (ASO-bcr). The mechanism was substantiated by Western blotting of the BCR-ABL expression level of CML cells, and the efficacy was substantiated by inhibition of colony formation compared with normal hematopoietic cells. The clonogenicity of K-562 cells expressing high levels of p210(BCR-ABL) was inhibited significantly by the ASO-bcr (T/C%, 30; P < 0.05) but not by ErPC3 (T/C%, 70). Combined sequential exposure to ErPC3 and the ASO-bcr, however, inhibited synergistically colony growth (T/C%, 3; P < 0.01). The colony growth of BV-173 cells expressing lower levels of p210(BCR-ABL) than K562 cells was inhibited to a greater extent by the ASO-bcr (T/C%, 15; P < 0.01). AR-230 cells that express high levels of p230(BCR-ABL) showed an intermediate decrease in colony formation in response to the ASO-bcr (T/C%, 20; P < 0.05). BCR-ABL levels of BV-173, CML-T1, and LAMA-84 cells were reduced in response to the ASO-bcr, as evidenced by Western blot. However, K-562 and AR-230 cells showed reduced BCR-ABL expression only after repeated treatment. ErPC3 and the ASO-bcr did not reduce colony formation (CFU-GM) of normal mouse bone marrow cells from long-term bone marrow cell cultures; instead, ErPC3 stimulated colony formation (P < 0.05) and did not induce chromosomal aberrations in mouse bone marrow. In conclusion, the combination of ErPC3 with a suitable antisense oligonucleotide inhibited synergistically colony formation of CML cell lines without damaging normal cells and thus might have a bearing on the purging of autologous hematopoietic transplants in CML patients.
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PMID:Combination with an antisense oligonucleotide synergistically improves the antileukemic efficacy of erucylphospho-N,N,N-trimethylpropylammonium in chronic myeloid leukemia cell lines. 1249 21

A large and diverse spectrum of oncogenes has been implicated as a contributor to angiogenesis in solid tumors based, in part, on its ability to induce proangiogenic growth factors such as vascular endothelial growth factor (VEGF), and the fact that various anti-oncogenic signaling inhibitor drugs have been shown to reverse such proangiogenic effects both in vitro and in vivo. Because leukemias are now also considered to be angiogenesis-dependent malignancies, we asked whether a similar paradigm might exist for the BCR-ABL oncogene and the Bcr-Abl targeting drug, STI-571 (imatinib mesylate), in the context of chronic myelogenous leukemia (CML) cells. We found that levels of VEGF expression in BCR-ABL-positive K562 cells were reduced in vitro by treatment with STI-571 in a dose-dependent fashion. Transfection of BCR-ABL into murine myeloid 32D and human megakaryocyte MO7e hematopoietic cells resulted in enhanced VEGF expression, which could be further elevated by the exposure to cytokines such as interleukin 3 and granulocyte macrophage colony-stimulating factor. We also found that conditioned media taken from 32D-p210-transfected cells could stimulate human umbilical vein endothelial cells by increasing phosphorylation of VEGF-R2/KDR and the downstream serine/threonine kinase PKB/Akt, an important regulator of endothelial cell survival. Moreover, amplification of BCR-ABL in STI-571-resistant cells was associated with elevated VEGF expression levels which could be reversed by treatment with higher concentrations of STI-571. Taken together, our results implicate BCR-ABL as a possible regulator of CML angiogenesis and raise the possibility that STI-571 could mediate some of its anti-CML properties in vivo through an angiogenesis-dependent mechanism.
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PMID:Imatinib mesylate (STI-571) reduces Bcr-Abl-mediated vascular endothelial growth factor secretion in chronic myelogenous leukemia. 1249 55

Chronic myeloid leukemia (CML) is characterized by expression of the BCR-ABL fusion gene that encodes a 210-kDa protein, which is a constitutively active tyrosine kinase. At least 70% of the oncoprotein is localized to the cytoskeleton, and several of the most prominent tyrosine kinase substrates for p210(BCR-ABL) are cytoskeletal proteins. Dendritic cells (DCs) are bone marrow-derived antigen-presenting cells responsible for the initiation of immune responses. In CML patients, up to 98% of myeloid DCs generated from peripheral blood mononuclear cells are BCR-ABL positive. In this study we have compared the morphology and behavior of myeloid DCs derived from CML patients with control DCs from healthy individuals. We show that the actin cytoskeleton and shape of CML-DCs of myeloid origin adherent to fibronectin differ significantly from those of normal DCs. CML-DCs are also defective in processing and presentation of exogenous antigens such as tetanus toxoid. The antigen-processing defect may be a consequence of the reduced capacity of CML-DCs to capture antigen via macropinocytosis or via mannose receptors when compared with DCs generated from healthy individuals. Furthermore, chemokine-induced migration of CML-DCs in vitro was significantly reduced. These observations cannot be explained by a difference in the maturation status of CML and normal DCs, because phenotypic analysis by flow cytometry showed a similar surface expression of maturation makers. Taken together, these results suggest that the defects in antigen processing and migration we have observed in CML-DCs may be related to underlying cytoskeletal changes induced by the p210(BCR-ABL) fusion protein.
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PMID:Dendritic cells from CML patients have altered actin organization, reduced antigen processing, and impaired migration. 1250 35

Natural killer (NK) cells decrease in function during chronic myelogenous leukemia (CML) progression from chronic phase to blast crisis, and they can become BCR/ABL(+) late in the disease course. To study this altered function, NK92 cells were transduced with the BCR/ABL oncogene. In contrast to the parental cells, which died when deprived of interleukin 2 (IL-2), p210(+) NK92 cells proliferated and survived indefinitely in the absence of IL-2. BCR/ABL also decreased the natural cytotoxicity of NK92 cells against K562 targets, without affecting IL-2, interferon gamma (IFN-gamma), or tumor necrosis factor alpha (TNF-alpha) production. Although the ABL-specific tyrosine kinase inhibitor imatinib mesylate (STI-571) had no effect on parental NK92 cells, it markedly decreased the growth and survival of IL-2-independent p210(+) NK92 cells. In contrast to the parental cell line, serial analysis of p210(+) NK92 cells detected small populations that clonally expressed one or more killer immunoglobulin-like receptors (KIRs). Unlike the decreased natural cytotoxicity, the function of the activating CD158j receptor remained intact. Southern blotting and hybridization with an enhanced green fluorescence protein (eGFP) probe showed that KIR(-) and KIR(+) NK92 cells were all derived from the same clone, suggesting that KIR acquisition remains dynamic at the maturational stage represented by the NK92 cell line. When tested in primary CD56(+bright) NK cells, p210 induced partial IL-2-independent growth and increased KIR expression similar to findings in NK92 cells. This is the first study to show that BCR/ABL, well known for its effects on the myeloid lineage, can alter the function of lymphoid cells, which may be associated with the defect in innate immunity associated with CML progression.
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PMID:BCR/ABL alters the function of NK cells and the acquisition of killer immunoglobulin-like receptors (KIRs). 1251 22

We describe a case of Philadelphia chromosome-positive chronic myeloid leukemia (Ph-positive CML) expressing p190(BCR-ABL). Reverse transcription-polymerase chain reaction (RT-PCR) analysis of bone marrow cells showed a 472-bp band using primers specific for the p190(BCR-ABL) but not p210(BCR-ABL) transcript. Sequencing analysis revealed that the PCR product was derived from the fusion between BCR exon e1 and ABL exon a2 (e1a2). CML expressing p190(BCR-ABL) is relatively rare. In a review of the literature, it may be grouped into 2 categories; approximately half of the patients exhibited prominent monocytosis and intermediate hematological phenotype between CML and chronic myelomonocytic leukemia, and the remaining patients showed no monocytosis.
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PMID:Philadelphia chromosome-positive chronic myeloid leukemia expressing p190(BCR-ABL). 1252 Nov 92

BCR-ABL fusion oncogene is the molecular hallmark of chronic myelogenous leukemia (CML), a condition characterized by a progression from a chronic to acute phase leukemia because of secondary genetic events, the nature of which remains largely unknown. Here, we report that the expression of the p210 BCR-ABL fusion protein leads to a down-regulation of BRCA1 protein, a gene product involved in the maintenance of genome integrity. BRCA1 protein is nearly undetectable in leukemia cells from patients with CML, both during the chronic phase and in blast crisis. Similarly, stable transfection-enforced expression of p210 protein in established hematopoietic cell lines leads to severe BRCA1 depletion. The lack of significant change in BRCA1 mRNA level in cells expressing p210 supports the hypothesis that the regulation of BRCA1 protein level occurs after transcription. It is abolished on exposure of the cells to STI571 and by mutation in the adenosine triphosphate (ATP) pocket of p210 and thus seems to require the tyrosine kinase activity of BCR-ABL. Cell lines expressing high levels of BCR-ABL display an increased rate of sister chromatid exchange and chromosome aberrations after ionizing radiation. These findings reveal a novel link between the oncoprotein BCR-ABL and the tumor-suppressor protein BRCA1.
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PMID:Down-regulation of BRCA1 in BCR-ABL-expressing hematopoietic cells. 1257 38

Despite increasing evidence on the formation of 1H NMR-detectable mobile lipid (ML) domains in cells induced to programmed cell death by continuous exposure to anticancer drugs, the time course of ML generation during the apoptotic cascade has not yet been fully elucidated. The present study shows that ML formation occurs at two different stages of apoptosis induced in human erythroleukemia K562 cells by a brief (3 hr) exposure to paclitaxel (Taxol), an antitumour drug with a stabilising effect on microtubules, or to paclitaxel plus tyrphostin AG957, a selective inhibitor of the p210(BCR-ABL) tyrosine kinase activity. A first wave of ML generation was in fact detected in paclitaxel-treated cells at the onset of the effector phase (8-24hr after exposure to the drug), plateaued at 24-48 hr and was eventually followed by further ML accumulation during the degradative phase (48-72 hr). Addition of AG957 to paclitaxel shifted to the 3-8 hr interval in both the early ML production and the onset of apoptotic events, such as chromatin condensation, phosphatidylserine externalization, cytochrome c release and caspase-3 activation. A significant loss of mitochondrial membrane potential was almost concomitant with the second wave of ML accumulation, associated in both cell systems with the phase of terminal cell degeneration, likely connected to non-regulated degradation of cell lipid components.
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PMID:Two-step formation of 1H NMR visible mobile lipids during apoptosis of paclitaxel-treated K562 cells. 1269 68

Both clinical and experimental evidence illustrate that p190 and p210 BCR/ABL oncogenic tyrosine kinases induce resistance to DNA damage and confer an intrinsic genetic instability. Here, we investigated whether BCR/ABL expression could modulate nucleotide excision repair (NER). We found that ectopic expression of p210 BCR/ABL in murine lymphoid BaF3 cell line inhibited NER activity in vitro, promoting hypersensitivity of these cells to ultraviolet (UV) treatment and facilitating a mutator phenotype. However, expression of p210 BCR/ABL in human and murine myeloid cell lines and primary bone marrow cells resulted in the increased NER activity and resistance to UV irradiation. The ABL tyrosine kinase inhibitor STI571 reversed these effects, showing that p210 BCR/ABL tyrosine kinase activity is responsible for deregulation of NER. Hypoactivity of NER in p210 BCR/ABL-positive lymphoid cells was accompanied by the decreased interaction between proliferating cell nuclear antigen (PCNA) and xeroderma pigmentosum group B (XPB); conversely, this interaction was enhanced in p210 BCR/ABL-positive myeloid cells. p190 BCR/ABL did not affect NER in lymphoid and myeloid cells. In summary, our study suggests that p210 BCR/ABL reduced NER activity in lymphoid cells, leading to hypersensitivity to UV and mutagenesis. In contrast, p210 BCR/ABL expression in myeloid cells facilitated NER and induced resistance to UV.
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PMID:p210 BCR/ABL kinase regulates nucleotide excision repair (NER) and resistance to UV radiation. 1282 1

Chronic myelogenous leukemia (CML) is characterized by a t(9;22) translocation resulting in expression of BCR-ABL fusion oncoproteins which are unique to the leukemic cells, necessary for oncogenesis, and potentially immunogenic. We have previously shown that human dendritic cells transduced with an adeno-associated virus vector encoding the fusion region of the b3a2 splice variant (p210(b3a2)) of the BCR-ABL oncoprotein elicit specific T-cell responses in vitro. Two cytotoxic T lymphocyte (CTL) clones generated in this fashion displayed restriction with previously unreported HLA alleles. The first, T1/B9, was CD4(+) and restricted by DRB5*0101 (autologous) or DRB1*1101 (allogeneic). The minimum cytotoxic epitope (MCE) binding to DRB5*0101 for this clone was identified as FKQSSKALQ, overlapping the p210(b3a2) fusion point (boldface). The MCE of DRB1*1101 for this clone differed from DRB5*0101, but also included the fusion point. The clonality of CTL T1/B9 was verified by analyses of TCRalpha/beta chain usage and DNA sequence analyses. To our knowledge, this is the first description of a single clone recognizing both DRB5*0101 and DRB1*1101. The other CTL clone, T1/33, was CD8+ and recognized HLA-B*3501 or B*3503 complexed with an MCE, RPVASDFEP, derived from the c-abl sequence in proximity to the p210(b3a2) fusion point. K562 cells transfected with plasmids encoding HLA-DRA + B5*0101, B*3501, or B*3503 but not controls expressing DRA + DRB1*1501 were lysed by cognate CTL clones, confirming that DRB5*0101 and B*3501/3 could present p210(b3a2) joining region epitopes via endogenous processing. The identification of three additional HLA alleles (DRB5*0101, B*3501, and B*3503) presenting the p210(b3a2) fusion-region antigen will broaden the application of vaccine strategies for targeting CML cells. The findings of single CTL clones cross-recognizing autologous (DRB5*0101 or B*3501) and allogeneic (DRB1*1101 or B*3503) HLA alleles presenting BCR-ABL fusion-region epitopes implies the potential separation of graft-versus-leukemia from graft-versus-host effects.
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PMID:Identification of new MHC-restriction elements for presentation of the p210(BCR-ABL) fusion region to human cytotoxic T lymphocytes. 1456 82


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