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)

The interactions between haemopoietic progenitor cells and marrow stromal cells that are essential for the regulation of normal haemopoiesis are defective in chronic phase chronic myeloid leukaemia (CML). The presence of primitive progenitor cells (blast colony-forming cells, Bl-CFC) in the blood of patients with CML is reflected by their reduced capacity to bind to marrow derived stromal layers in vitro. Whereas normal bone marrow Bl-CFC bind irreversibly to cultured stromal layers (and none are found in normal blood), the Bl-CFC in CML bind transiently and then detach. The normal cell adhesion mechanism is partially sensitive to treatment with phosphatidylinositol-specific phospholipase C (Pl-PLC), indicating the participation of a phosphatidylinositol (Pl)-linked structure; however, when CML cells were treated with Pl-PLC it had no effect on progenitor binding. Two other Pl-linked structures, decay-accelerating factor (DAF) and lymphocyte function associated antigen-3 (LFA-3) were normally expressed on CD34 positive CML cells and normally susceptible to Pl-PLC treatment. The treatment of normal cells with Pl-PLC, to mimic the situation in CML, resulted in the indiscriminate and inefficient binding of Bl-CFC to stroma. Moreover, treatment of the normal cells with 5637 conditioned medium (CM), which contains haemopoietic growth factors, also reduced the binding capacity of normal Bl-CFC; 5637CM treatment did not alter the expression of DAF. It is proposed that a Pl-linked cell adhesion molecule (CAM) is deficient in CML as a consequence of the constitutive activation of ABL kinase whilst, in normal cells, CAMs attached in this manner are responsible for efficient adhesion to stroma and are regulated by growth factors.
Leukemia 1991 Aug
PMID:Deficiency of a phosphatidylinositol-anchored cell adhesion molecule influences haemopoietic progenitor binding to marrow stroma in chronic myeloid leukaemia. 171 60

To determine the role of the BCR-ABL gene in the proliferation of blast cells of patients with chronic myelogenous leukemia, leukemia blast cells were exposed to synthetic 18-mer oligodeoxynucleotides complementary to two identified BCR-ABL junctions. Leukemia colony formation was suppressed, whereas granulocyte-macrophage colony formation from normal marrow progenitors was unaffected. When equal proportions of normal marrow progenitors and blast cells were mixed, exposed to the oligodeoxynucleotides, and assayed for residual colony formation, the majority of residual cells were normal. These findings demonstrate the requirement for a functional BCR-ABL gene in maintaining the leukemic phenotype and the feasibility of gene-targeted selective killing of neoplastic cells.
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PMID:Selective inhibition of leukemia cell proliferation by BCR-ABL antisense oligodeoxynucleotides. 185 87

A patient is described with de novo acute non-lymphocytic leukemia of megakaryoblastic lineage with tri-lineage myelodysplasia. This patient was studied cytogenetically and using molecular genetic techniques throughout her clinical course. She had an N-ras mutation at diagnosis which persisted despite a bone marrow transplant, and acquired a Philadelphia chromosome associated with a P190 BCR-ABL transcript at clinical relapse 3 months post-transplantation.
Leukemia 1991 Aug
PMID:Megakaryoblastic leukemia with an N-ras mutation and late acquisition of a Philadelphia chromosome. 188 21

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

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.
Leukemia 1991 Oct
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.
Leukemia 1991 Nov
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 chromosome (Ph) is the cytogenetic hallmark of chronic myeloid leukemia (CML) and as such has been used to confirm the diagnosis of CML based on morphological and clinical criteria. We have investigated 12 patients who were considered to have clinical and morphological features of CML and who did not have detectable abnormalities of chromosomes 9q34 or 22q11. In six of the 12 patients, rearrangement within the 5.8 kb major breakpoint region (M-bcr) and amplification of CML specific M-bcr-ABL cDNA sequences by the polymerase chain reaction (PCR) was demonstrated. Six other CML patients did not have rearrangement of the M-bcr gene or amplification of BCR-ABL by PCR. These patients had atypical CML. They were significantly older, most had less than 10% immature granulocytic cells (metamyelocytes, myelocytes and promyelocytes) and had various degrees of marrow fibrosis. Three of these six patients died of blastic transformation at 4, 15 and 54 months from diagnosis.
Leukemia 1991 Mar
PMID:Molecular diagnosis of Philadelphia negative CML using the polymerase chain reaction and DNA analysis: clinical features and course of M-bcr negative and M-bcr positive CML. 201 77

The Philadelphia translocation in chronic myelogenous leukemia (CML) results in the production of a 210 kD BCR-ABL protein. In contrast, in 50% of Philadelphia-positive acute leukemias, the translocation results in the production of a 190 kD BCR-ABL protein. To investigate the hypothesis that the production of P190 may be associated with the progression from chronic phase to blast crisis in CML, we used polymerase chain reaction to analyze blood from 37 patients with accelerated phase/blast crisis CML for the transcripts coding for the P210BCR-ABL and P190BCR-ABL. The mRNA encoding for P210 was detected in all patients. In three patients, mRNA encoding both P210 and P190 was present. In two of these three patients, samples were available from the time of initial diagnosis. Analysis of these samples did not reveal any transcripts for P190. We conclude that in some patients the appearance of P190BCR-ABL may correlate with transformation to a more aggressive, terminal phase of CML.
Leukemia 1991 Mar
PMID:Appearance of acute leukemia-associated P190BCR-ABL in chronic myelogenous leukemia may correlate with disease progression. 201 78

The characteristic genetic exchange in chronic myeloid leukemia (CML) is the fusion of the ABL proto-oncogene and a specific part of the BCR or phl gene. Detection of this exchange by cytogenetic or Southern blot analysis is highly diagnostic for CML. The latter approach has not previously been used to quantify the relative proportions of leukemic and non-leukemic cells. We have assessed the feasibility of estimating the relative proportion of leukemic cells present in a sample by densitometric analysis of autoradiographs of Southern blots. In dilution experiments of CML cells with normal cells, a linear relationship could be demonstrated between the relative intensity of the autoradiograph band corresponding bcr rearrangement and the proportion of leukemic cells present. This relationship was found to be largely independent of autoradiograph exposure time. Six patients receiving various therapies have been evaluated for as long as 4.5 years by repeated densitometric and cytogenetic analysis. In general, a declining proportion of Philadelphia (Ph) chromosome positive cells was paralleled by decreasing intensity of the autoradiograph band representing bcr rearrangement. Densitometric changes were often seen prior to the detection of Ph negative cells. This analysis appears to provide a sensitive method for monitoring patients with CML.
Leukemia 1991 Jul
PMID:Densitometric analysis of Southern blot autoradiographs and its application to monitoring patients with chronic myeloid leukemia. 207 39

We studied the cells from three selected patients with Ph-chromosome-negative chronic myeloid leukemia (CML) by Southern blotting, polymerase chain reaction, and in situ hybridization of informative probes to metaphase chromosomes. All three patients had rearrangement of M-BCR sequences in the BCR gene and expression of one or other of the mRNA species characteristic of Ph-positive CML. Leukemic metaphases studied after trypsin-Giemsa banding were indistinguishable from normal. The ABL probe localized both to chromosome 9 and 22 in each case. A probe containing 3' M-BCR sequences localized only to chromosome 22, and not to chromosome 9 as would be expected in Ph-positive CML. Two new probes that recognize different polymorphic regions distal to the ABL gene on chromosome 9 in normal subjects localized exclusively to chromosome 9 in two patients and to both chromosomes 9 and 22 in one patient. These results show that Ph-negative CML with BCR rearrangement is associated with insertion of a variable quantity of chromosome 9 derived material into chromosome 22q11; there is no evidence for reciprocal translocation of material from chromosome 22 to chromosome 9.
Leukemia 1990 Apr
PMID:Interstitial insertion of varying amounts of ABL-containing genetic material into chromosome 22 in Ph-negative CML. 216 19


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