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)

We used fluorescence in situ hybridization (FISH) to metaphase chromosomes with BCR and ABL cosmid probes in conjunction with the polymerase chain reaction (PCR) to study the mechanism by which the ABL proto-oncogene is inserted into a morphologically normal chromosome 22 in patients with Ph-negative chronic myeloid leukaemia characterized by the BCR-ABL chimeric gene. In control patients with Ph-positive CML the ABL probe localized to 22q- and the 3' BCR probe localized to 9q+. In nine Ph-negative CML patients the ABL probe localized to one normal chromosome 9 and to one 'normal' chromosome 22. Both 5' and 3' BCR probes localized exclusively to the chromosomes 22. By PCR all had evidence of BCR-ABL transcripts, but none had evidence of the reciprocal ABL-BCR gene product that is seen in 70% of the Ph-positive CML patients. These data confirm the view that Ph-negative CML results from insertion of ABL-containing DNA sequences into a normal-appearing chromosome 22 without reciprocal translocation of sequences from chromosome 22 to chromosome 9.
Leukemia 1994 Mar
PMID:Lack of reciprocal translocation in BCR-ABL positive Ph-negative chronic myeloid leukaemia. 812 50

The region comprised between the amino acids 175 and 199 of the HTLV-I envelope surface glycoprotein is one of the immunodominant domains of this molecule. In this region, which is well recognized by sera from HTLV-I infected patients, a substitution of the proline at position 192 by a serine has been described in some isolates. Because this mutation could modify the secondary structure of the glycoprotein molecule, we studied the inference of the presence of proline or serine on the recognition of the region 175-199 by human sera. For this, three peptides have been synthetized (a 25-mer 175-199 corresponding to the sequence of the ATK prototype, and two internal 10-mer 190-Pro-199 and 190-Ser-199 having a proline or a serine at position 192) and tested by immunosorbent assay. While most sera reacted with 190-Pro-199 and with 190-Ser-199 synthetic peptides, a differential recognition was observed according to the pathology associated to HTLV-I infection. Moreover sera corresponding to patients infected with a virus harboring a serine at position 192 were found to recognize only the 10-mer with a serine. These data indicates that HTLV-I is subject to antigenic variability.
Leukemia 1994 Apr
PMID:Recognition by human sera of a variable region of the surface glycoprotein of HTLV-I. 815 6

With a seroprevalence rate (SPR) of 6%-10% among healthy adult blood donors (ABD), Nigeria and other African locales represent an endemic zone for HTLV-I. We studied SPR in patients with leukaemia, lymphomas, solid tumours, and chronic disorders, as well as in groups of men and women with varying sexual lifestyles. Serum specimens were screened with ELISA and then confirmed with Western blot (WB). Sexual practices were investigated among volunteers of different sexual backgrounds by means of a questionnaire. Female prostitutes (FP) (13.0%) and patients with sexually transmitted diseases (STDP) (16.7%) had the highest SPR while a low rate occurred in religious celibate males (RCM) but not in religious celibate females (RCF) (11.8%). Heterosexual activity as well as geographical location of the place of birth constituted the most important risk factors for HTLV-I. HIV antibodies were demonstrable in none of the study subjects. ATL was associated with 100% SPR (4/4) while SPR in other clinical states were not different from normal. Western blot profile was rarely of strong poly band but more frequently of weak oligo band pattern with absent or weak p19 compared to p24. Only 18% of non Hodgkin's lymphoma in Ibadan, Nigeria was seropositive compared to 50% and > 60% in Japanese and Caribbean endemic zones respectively. The high SPR and aberrant WB profiles indicate reactivity to HTLV-I and to an HTLV-II-like activity, probably a new virus in the region. Excluding the aberrant WB profile, SPR based on HTLV-I-related profile was 3.8%-4.8% in ABD, 13% in FP, 10% in STDP, 1.9% in RCM, 0% in RCF, and 25% in ATL patients. The HTLV-II-related profile showed no such heterosexual association, but occurred in 75% of ATL patients. HTLV-I and probably and an HTLV-II-like virus appear to play a role in STD and lymphoma epidemiology in Nigeria.
Leukemia 1994 Apr
PMID:Some epidemiological features of the human T-cell lymphotropic virus type I (HTLV-I) and ATL in Nigerians. 815 10

Chronic myelogenous leukemia (CML) is associated with a translocation of the BCR and the ABL genes, t(9;22). Results of this event are transcription and translation products that are unique to malignant cells. We therefore designed synthetic ribozymes which are capable of exclusively cleaving the BCR/ABL B3A2-type mRNA without altering normal cellular transcripts. Synthetic B3A2-type transcripts could only be cleaved by B3A2-type mRNA targeted ribozymes and not by any of the controls. The B3A2-type mRNA directed ribozyme, on the other hand, did not cleave any of the control transcripts. The effective delivery of ribonucleic acids by lipofection into K562 cells could be demonstrated by fluorescent microscopy, slot blot analysis, and RNA polyacrylamide gel electrophoresis. In vivo, we were able to induce a significant inhibition of the proliferation of K562 cells with ribozymes directed against the B3A2-type mRNA. Quantitative PCR analyses showed an up to fivefold reduction of the relative number of BCR/ABL mRNA molecules per single cell after exposure to ribozymes compared to controls. We conclude that ribozymes targeted against the B3A2-type BCR/ABL mRNA function in vitro and in vivo.
Leukemia 1993 Nov
PMID:In vitro and in vivo effects of synthetic ribozymes targeted against BCR/ABL mRNA. 823 Dec 47

Constitutive activation of BCR-ABL tyrosine kinase fusion protein has been shown to be an essential step in the pathogenesis of Philadelphia chromosome (Ph)-positive leukemias. We studied the tyrosine phosphorylated proteins which might be involved in the signaling pathway p185BCR-ABL using a Ph-positive acute lymphoblastic leukemia cell line. p185BCR-ABL but not p145c-abl was constitutively phosphorylated on tyrosine in this cell line. p21ras GTPase-activating protein (GAP) was physically associated with p185BCR-ABL, but not with p145c-abl, and GAP-associated proteins p62/p190 were found to be tyrosine-phosphorylated. Furthermore, p185BCR-ABL was also physically associated with phospholipase C-gamma 1 (PLC-gamma) and phosphatidylinositol 3'-kinase (P13-kinase). Concomitantly, both PLC-gamma and p85 subunit of P13-kinase are tyrosine-phosphorylated in the cells with p185BCR-ABL. These data suggest that GAP, GAP-associated proteins, PLC-gamma, and P13-kinase may participate in downstream signaling for p185BCR-ABL tyrosine kinase.
Leukemia 1994 Jan
PMID:Potential molecules implicated in downstream signaling pathways of p185BCR-ABL in Ph+ ALL involve GTPase-activating protein, phospholipase C-gamma 1, and phosphatidylinositol 3'-kinase. 828 76

BCR-ABL antisense oligonucleotides can specifically reduce colony formation of early hematopoietic progenitor cells from chronic myeloid leukemia (CML) patients. Little is known about the mechanism of this inhibition. We studied the inhibition of the bcr-abl oncogene using fluorescein-labeled phosphorothioate oligonucleotides in the Philadelphia chromosome-positive cell line BV173. Oligonucleotide stability, uptake, bcr-abl mRNA degradation, inhibition of cell proliferation, and cell death were studied. The oligonucleotide uptake was directly dependent on the extracellular concentration and was constant over the first 18 h of incubation. After that the uptake rate decreased. We detected a decrease in bcr-abl mRNA after 3 days of treatment with antisense oligonucleotides, but much less in controls. The controls used in the experiments were the sense oligonucleotide, equimolar amounts of sense and antisense, and an untreated control. Antisense oligonucleotides completely inhibited cell growth of BV173 cells and did not inhibit growth of HL-60 cells, whereas control oligonucleotides had no such effect on either cell line. An oligonucleotide specific for the other CML breakpoint was also effective in reducing cell growth of BV173. By the use of a DNA double staining technique to discriminate between necrotic and apoptotic cells, we detected a large number of apoptotic cells in antisense treated BV173 cultures after 5 days of treatment as compared to controls. We conclude that antisense BCR-ABL oligonucleotides reduce bcr-abl mRNA expression in BV173 cells mainly in a sequence-specific manner and induce apoptosis.
Leukemia 1994 Jan
PMID:Antisense BCR-ABL oligonucleotides induce apoptosis in the Philadelphia chromosome-positive cell line BV173. 828 78

A rapid and simple polymerase chain reaction (PCR) method is described that is capable of identifying any of the BCR-ABL transcripts that have yet been described in chronic myeloid or acute lymphoblastic leukaemia. Randomly primed cDNA is synthesized from leucocyte RNA and amplified in a single reaction containing four oligonucleotide primers (multiplex PCR). Different size products are generated from ela2 (p190) and b3a2 or b2a2 (p210) BCR-ABL transcripts which are readily and unambiguously distinguishable after agarose gel electrophoresis without the need for either nested PCR or hybridization. Chronic myeloid leukaemia cells are readily detectable even when diluted 1 in 1000 with normal blood. Samples which do not have BCR-ABL rearrangements produce a single band derived from the normal BCR gene, and the presence of this band controls for adequate RNA and cDNA preparation. Using this assay we have detected BCR-ABL transcripts in a variety of haematological disorders.
Leukemia 1994 Jan
PMID:An optimized multiplex polymerase chain reaction (PCR) for detection of BCR-ABL fusion mRNAs in haematological disorders. 828 86

Two-thirds of patients with Philadelphia (Ph) chromosome-positive acute lymphoblastic leukaemia (ALL) have a breakpoint in the minor breakpoint cluster region (m-bcr) of the BCR gene, which results in an e1a2 transcript and a P190BCR-ABL fusion protein. This type of genomic rearrangement occurs very rarely in chronic myeloid leukaemia (CML); it has been reported in only four cases. We describe here a fifth case of P190 CML in which the cytomorphological characteristics were intermediate between CML and chronic myelomonocytic leukaemia (CMML). This case, and the four reported previously, had a consistent and significant monocytosis with a low neutrophil/monocyte ratio in the peripheral blood, resembling CMML. On the other hand, they also had a high percentage of circulating immature granulocytes, basophilia and low neutrophil alkaline phosphatase (NAP) score, which are more commonly found in classical CML. Thus, P190 CML may be a specific form of CML, in which the myeloproliferative process includes the monocytic, as well as the granulocytic lineage. Since the molecular defect in CML is thought to involve a pluripotent stem cell, the different effects of P210BCR-ABL and P190BCR-ABL in CML must reflect the somewhat wider spectrum of activity of the P190BCR-ABL. Other patients with atypical CML or CMML who lack a Ph chromosome may also have an m-bcr breakpoint which would not be detected on standard Southern blots, but which would be detectable by polymerase chain reaction amplification of reverse transcribed RNA.
Leukemia 1994 Jan
PMID:P190BCR-ABL chronic myeloid leukaemia: the missing link with chronic myelomonocytic leukaemia? 793 80

We performed cytogenetic and molecular analysis of the BCR-ABL rearrangement by polymerase chain reaction (PCR) in 39 consecutive cases of adult acute lymphoblastic leukemia (ALL). Eleven patients had a Philadelphia (Ph) chromosome. Thirteen patients had a BCR-ABL rearrangement, involving minor breakpoint cluster region (m-bcr, situated in intron 1 of the BCR gene) in 11 cases, and major breakpoint cluster region (M-bcr, 'specific' of chronic myeloid leukemia) in the remaining two cases. All of the 12 BCR-ABL cases studied immunologically were of early B, CALLA-positive immunophenotype. The 13 BCR-ABL positive cases included the 11 Ph-positive cases, and two patients with normal karyotype at diagnosis. In the two Ph-negative BCR-positive cases, seven (patient 1) and 18 (patient 2) mitoses had been examined at diagnosis. In patient 1, Ph negativity at diagnosis could certainly be explained by the small number of mitoses analyzed, as a Ph chromosome was found at relapse. This was less probable in patient 2, who raised the issue of whether authentic Ph-negative BCR-ABL-positive ALL exists (as in the chronic myeloid leukemia model) or not. Whatever the explanation, our results suggest that molecular detection of BCR-ABL should be more widely used in B-lineage ALL.
Leukemia 1993 Jul
PMID:Philadelphia negative, BCR-ABL positive adult acute lymphoblastic leukemia (ALL) in 2 of 39 patients with combined cytogenetic and molecular analysis. 832 Oct 20

We have analyzed the M-bcr breakpoint position in 133 Philadelphia-positive chronic myeloid leukemia patients and correlated the findings with clinical, hematologic, and cytogenetic data. We also investigated the splicing pattern of the BCR-ABL mRNA in 30 patients, using reverse transcriptase PCR. No statistically significant differences were found between breakpoint position within M-bcr and clinical parameters at diagnosis, the karyotypic evolution pattern, or the leukemic phenotype during blast crisis. Furthermore, the breakpoint position within M-bcr did not correlate with the duration of chronic phase or survival time. When the splicing pattern of the BCR-ABL mRNA was compared with the results of the genomic breakpoint mapping, it was found that approximately 60% (8/14) of the patients with a 5' break expressed b2a2 fusion mRNA, whereas all patients (10/10) with a 3' break expressed b3a2 BCR-ABL mRNA.
Leukemia 1993 Aug
PMID:Clinical impact of breakpoint position within M-bcr in chronic myeloid leukemia. 835 Jun 22


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