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)

Interferon (IFN) therapy has become widely used for the treatment of chronic myelogenous leukemia. Hematologic remissions can be induced in about 60% of patients. Moreover, in a small number of patients loss of the Philadelphia (Ph) chromosome and of the BCR-ABL rearrangement is observed. We have used genomic Southern blotting as well as a two-step polymerase chain reaction (PCR) method to score for BCR-ABL messenger RNA (mRNA) in patients with hematologic remission induced by treatment with IFN alpha-2b alone or in combination with IFN gamma. Concomitantly, cytogenetic analysis was performed. In 11 of 115 patients reported here, a complete loss of rearranged BCR fragments was observed in Southern blots of peripheral blood (PB) and/or bone marrow (BM) cell samples. Malignant marker bands disappeared first in the PB. In six patients, this genotype remained stable, whereas in five patients, low-intensity, rearranged bands reappeared despite continuation of treatment. The reappearance of the malignant marker was not accompanied by a clinical relapse. Ph-negative metaphases were observed in PB cells of four patients and in the PB and BM cells of two of these patients. In the samples of the other patients, residual Ph-positive cells were detected. By two-step PCR, residual BCR-ABL rearranged transcripts were found in samples of 10 patients.
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PMID:Minimal residual disease in patients with chronic myelogenous leukemia undergoing long-term treatment with recombinant interferon alpha-2b alone or in combination with interferon gamma. 193 40

Leukemia cells from adults with Philadelphia (Ph1)-chromosome positive chronic myelogenous leukemia (CML) have a characteristic molecular rearrangement between the BCR and ABL genes whereby major breakpoint cluster region (Mbcr) exons 2 or 3 are joined to ABL exon II. Ph1-chromosome positive CML is uncommon in children and it is unknown whether these children have similar rearrangements. We studied 17 children with Ph1-chromosome positive CML. Five were studied for Mbcr rearrangement using Southern blotting, nine for the presence of chimeric BCR-ABL mRNA using reverse transcription and polymerase chain reaction, and three for both. All eight children studied by Southern blotting had BCR rearrangement. Of 12 children in whom BCR-ABL mRNA was studied, 10 had Mbcr exon 2 joined to ABL exon II, one had Mbcr exon 3 joined to ABL II, and one had both Mbcr-ABL junctions. These data indicate a similarity to adult CML. However, mRNA processing in children may preferentially splice Mbcr exon 2 to ABL exon II. No child had BCR exon 1 joined to ABL exon II, the rearrangement typical of childhood Ph1-chromosome positive acute lymphoblastic leukemia.
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PMID:BCR-ABL rearrangements in children with Philadelphia chromosome-positive chronic myelogenous leukemia. 193 52

Chromosome in situ hybridization studies showed that the normal karyotype of leukemic cells from a patient with Ph1-negative, BCR-positive chronic myeloid leukemia (CML) concealed a complex t(9;22;20)(q34;q11;p13). The close association of 5'-BCR and 3'-ABL was demonstrated by field inversion gel electrophoresis, and in situ hybridization showed that BCR-ABL was located on the short arm of chromosome 20. Our findings further indicate that chromosome rearrangement is the cause of BCR-ABL gene fusion in leukemic cells that show a normal karyotype. Results from in situ hybridization studies were consistent with formation of the t(9;22;20) by a two step chromosomal rearrangement, but field inversion gel electrophoresis results indicated a more complex rearrangement.
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PMID:A complex chromosome rearrangement forms the BCR-ABL fusion gene in leukemic cells with a normal karyotype. 195 92

The Philadelphia1 (Ph1) chromosome results from a reciprocal translocation between chromosome 9 and chromosome 22, which fuses a portion of the ABL oncogene to the BCR gene, forming the BCR/ABL fusion gene. This produces a fusion protein with a greatly increased protein tyrosine kinase activity in comparison to that of the normal ABL protein. The BCR/ABL gene is transcribed from the promoter of the normal BCR gene, but little is known about the regulation of its expression. In this study, we asked whether there are sequence-specific DNA-binding proteins (DBP) that bind to the breakpoint cluster region (bcr, or Mbcr) within the BCR gene. Sequence-specific DBP located within the Mbcr could have a transcription-regulating effect, and they could participate in the recombination that generates BCR/ABL. Our data show that there are sequence-specific DBP that bind within the Mbcr.
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PMID:Sequence-specific DNA-binding proteins within the Mbcr on the Ph1 chromosome. 195 95

Previous studies have revealed a consistent defect in the cycling behavior of primitive neoplastic progenitor cells in patients with Philadelphia chromosome (Ph1)-positive chronic myeloid leukemia (CML). This is manifested both in vivo and in long-term cultures of CML cells as an increased rate of turnover amongst Ph1-positive progenitor cell types whose counterparts in normal individuals are mainly quiescent. To determine whether this deregulated proliferative activity of primitive Ph1-positive cells might be explained by a perturbation in the production of growth factors that regulate the turnover of primitive normal cells, the possibility of either autocrine or paracrine mechanisms of Ph1-positive cell stimulation was investigated. Northern blot analysis of total cellular RNA extracted from various CML blood cell populations showed no evidence of increased expression of granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage-CSF (GM-CSF), interleukin-1 alpha (IL-1 alpha), IL-1 beta, IL-3, IL-6, or tumor necrosis factor-alpha (TNF-alpha) compared with analogous normal peripheral blood cell populations in which transcripts for most of these growth factors are not detectable. A similar analysis of RNA extracted from the adherent layer of 4-week-old long-term cultures established from CML marrow (in which the Ph1-positive cells typically disappear) or from CML blood seeded onto normal marrow adherent layers (in which Ph1-positive cells typically persist) also revealed no difference in growth factor production compared with analogous cultures established with exclusively normal cells. For some of the growth factors studied, the assessment of bioactivity detectable in the medium confirmed the RNA data. There was also no evidence of a decreased production of putative inhibitors of primitive hematopoietic cells, i.e. transforming growth factor-beta and macrophage inflammatory protein-1 alpha by CML versus normal cells or cultures. These results do not support the existence of BCR-ABL induced autocrine or paracrine mechanisms in CML and suggest that constitutive activation of events normally dependent on growth factor receptor stimulation is more likely to underlie the lack of proliferation control exhibited by primitive Ph1-positive cells.
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PMID:Lack of evidence for abnormal autocrine or paracrine mechanisms underlying the uncontrolled proliferation of primitive chronic myeloid leukemia progenitor cells. 196 Oct 20

The BCR gene, on chromosome 22, is involved in the Philadelphia (Ph1) chromosome which is a characteristic cytogenetic marker of chronic myeloid leukaemia (CML). Breakpoints in CML occur within the M-bcr region (5.8 kb) which encompasses exons 12-15 (b1-b4), and the M-bcr can be conveniently divided into five zones by restriction mapping. One of these zones (3) contains exon b3 which can be either present or absent from the hybrid mRNA, even if it is present in the chimaeric gene. We have mapped the breakpoints around BCR exon b3 and related this to the type of RNA splice site expressed, in CML patients at diagnosis. Breakpoints within zone 3 were restriction mapped to one of six sub-zones and the site related to the type of RNA splice site. Two clusters of breakpoints within zone 3 were observed. One cluster was located around exon b3 and often resulted in deletion of exon b3 from the chimaeric gene. The majority of this cluster expressed b2-a2 spliced RNA, usually as a consequence of a deletion removing exon b3. The second cluster occurred within two sub-zones that spanned an Alu sequence, and 90% of this cluster exhibited b3-a2 spliced RNA. Furthermore, a greater number of patients had entered blast crisis if the RNA contained BCR exon b3 (8 of 10 patients), compared to those with b2-a2 spliced RNA (3 of 12 patients). The high degree of heterogeneity in the site of the breakpoint within zone 3 of the M-bcr, combined with the type of BCR-ABL hybrid mRNA expressed, further implicates BCR exon b3 in the pathogenesis of CML.
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PMID:Mapping of breakpoints, and relationship to BCR-ABL RNA expression, in Philadelphia-chromosome-positive chronic myeloid leukaemia patients with a breakpoint around exon 14 (b3) of the BCR gene. 196 Oct 34

The Philadelphia (Ph1) chromosome is present in greater than 90% of patients with chronic myelogenous leukemia (CML) and in 2% to 20% of those with acute leukemias, for which it is an important prognostic marker too. The chimeric BCR-ABL mRNAs resulting from the translocation encode either a 210-Kd or a 190-Kd protein. The techniques used to detect Ph1 chromosome include karyotyping, Southern analysis to demonstrate bcr rearrangement, and polymerase chain reaction to amplify the BCR-ABL transcripts. However, the routine performance of these methods by clinical laboratories is cumbersome, time consuming, and exposes laboratory personnel to radioisotopes. We describe here the clinical application of a new method, the hybridization protection assay (HPA), which uses chemiluminescent acridinium-ester-labeled probes in conjunction with PCR for detection of the amplified BCR-ABL sequences. The method is sensitive, specific, and can reliably distinguish between the transcripts for P190BCR-ABL and P210BCR-ABL. In contrast to the 2 days or longer required for conventional hybridization, HPA analysis can be completed in less than 30 minutes. We have successfully used this method to analyze 60 leukemia samples (34 from Ph1-negative acute leukemias; 6 from Ph1-positive acute leukemias; and 20 from CML) with complete correlation (of BCR-ABL positivity or negativity) with the results of karyotype or Southern Blot analysis of genomic DNA for bcr rearrangement. Therefore, the HPA, in conjunction with PCR, appears to provide a rapid and reliable test for the diagnosis of Ph1-positivity.
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PMID:Hybridization protection assay: a rapid, sensitive, and specific method for detection of Philadelphia chromosome-positive leukemias. 198 90

Interleukin-7 (IL-7) is a potent stimulator of pre-B-lymphocyte proliferation. Pre-B cells transformed by a variety of oncogenes including those of the ABL protein tyrosine kinase family were screened for endogenous IL-7 mRNA expression by polymerase chain reaction and a sensitive bioassay for secreted IL-7. Some v-abl but none of the BCR/ABL, v-src, v-fms, v-myc, v-ras, or v-raf transformants analyzed contained elevated IL-7 transcripts. None of the cell lines secreted detectable bioactivity. We overexpressed IL-7 via a retroviral vector in an IL-7-dependent pre-B cell line to assess the potential for autocrine growth stimulation and malignant transformation. We achieved dramatic deregulation of IL-7 translational suppression by removing portions of the 5' flanking region. Levels of IL-7 expression much greater than those needed to establish factor-independent growth did not induce colony formation in agar by IL-7-expressing pre-B cell lines, and the majority of these lines were nontumorigenic in syngeneic mice. The same pre-B cell line transformed by v-abl displayed a highly malignant phenotype while containing dramatically lower IL-7 transcript levels. We conclude that endogenous IL-7 expression is not a necessary event in transformation of pre-B cells, nor is it sufficient to explain the malignant phenotype in v-abl-transformed cells. Up regulation of endogenous IL-7 expression in some transformed pre-B cells may be one of several synergistic events which can lead to malignant conversion.
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PMID:Hyperexpression of interleukin-7 is not necessary or sufficient for transformation of a pre-B lymphoid cell line. 199 Feb 88

The translocation between chromosome 9 and chromosome 22 which creates the Philadelphia chromosome moves the ABL oncogene from its normal location on chromosome 9 and fuses it with a portion of the BCR gene on chromosome 22. This new BCR/ABL fusion gene generates a unique 8.7 kilobase (kb) RNA which codes for a new 210 kilodalton (kd, p210) protein which has a protein tyrosine kinase activity that is greatly increased in comparison to the normal ABL protein. The human K562 cell line was derived from a patient with CML, and serves as one model for the regulation of expression of the ABL and BCR/ABL genes. This study examines the expression of the BCR/ABL fusion gene and the normal ABL gene in relation to differentiation and changes in proliferative state. The expression of both the normal ABL transcripts and the BCR/ABL fusion transcript decrease approximately ten-fold when the cells are induced to differentiate with hemin. In contrast, expression of the MYC oncogene is unaffected by hemin-induced differentiation. The results suggest that both ABL and BCR/ABL expression vary in proportion to the differentiation of the cells, but minimally if at all as a function of the cells' proliferative state.
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PMID:ABL oncogene expression during erythroleukemia cell differentiation. 199 45

The c-abl proto-oncogene encodes a cytoplasmic tyrosine kinase which is homologous to the src gene product in its kinase domain and in the upstream kinase regulatory domains SH2 (src homology region 2) and SH3 (src homology region 3). The murine v-abl oncogene product has lost the SH3 domain as a consequence of N-terminal fusion of gag sequences. Deletion of the SH3 domain is sufficient to render the murine c-abl proto-oncogene product transforming when myristylated N-terminal membrane localization sequences are also present. In contrast, the human BCR/ABL oncogene of the Philadelphia chromosome translocation has an intact SH3 domain and its product is not myristylated at the N terminus. To analyze the contribution of BCR-encoded sequences to BCR/ABL-mediated transformation, the effects of a series of deletions and substitutions were assessed in fibroblast and hematopoietic-cell transformation assays. BCR first-exon sequences specifically potentiate transformation and tyrosine kinase activation when they are fused to the second exon of otherwise intact c-ABL. This suggests that BCR-encoded sequences specifically interfere with negative regulation of the ABL-encoded tyrosine kinase, which would represent a novel mechanism for the activation of nonreceptor tyrosine kinase-encoding proto-oncogenes.
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PMID:BCR first exon sequences specifically activate the BCR/ABL tyrosine kinase oncogene of Philadelphia chromosome-positive human leukemias. 200 81


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