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PubMed2000

Detection of BCR-ABL transcripts by multiplex and nested PCR in different haematological disorders.

Single-step Multiplex RT-PCR was used as a rapid and highly sensitive method for screening patients with myeloproliferative conditions and ALL for the presence of underlying BCR-ABL gene fusions. Positive and negative results obtained with the multiplex assay were subsequently confirmed by nested PCR. We studied 21 patients for detecting the presence of b3a2, b2a2 and e1a2 BCR-ABL transcripts at diagnosis and following treatment with different therapeutical procedures. These studies allowed the molecular characterisation of patients with different haematological disorders and for demonstrating BCR-ABL transcripts in Ph-CML. In a Ph+ CML patient, a switch of isoforms was detected after bone marrow transplantation and infusion with donor lymphocytes, implying substitution of e1a2 for b3a2 coexisting with a myeloid/lymphoid biphenotypic profile. In ALL, one Ph+ patient showed coexpression of e1a2 and b2a2 at diagnosis followed by persistence of e1a2 after bone marrow transplantation. Our results were compared to previous findings in the literature on molecular diagnosis of leukaemias.

DNA, Complementary↗
PubMed1993

Inhibition of phosphorylation of p160 BCR within p210 BCR-ABL complexes during early stages of phorbol ester-induced differentiation of K562 cells.

The kinase activity of the BCR-ABL gene product is known to be down-regulated in K562 cells treated with low concentrations of the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA). The reduction of BCR-ABL kinase activity is followed by the loss of cell proliferation and progression to a more differentiated state. We have previously demonstrated that K562 cells possess protein complexes that contain p210 BCR-ABL and p160 BCR (M. L. Campbell, W. J. Li, and R. B. Arlinghaus, Oncogene, 5: 773-776, 1990). We performed experiments to determine whether BCR-ABL/BCR complexes were disrupted prior to alterations in cell growth and differentiation effects in TPA-treated K562 cells. Our results indicate that BCR-ABL/BCR complexes disappeared at precisely the same time after TPA treatment as the loss of autophosphorylation activity exhibited by total p210 BCR-ABL, which occurred 16-19 h after TPA treatment. The loss of kinase activity preceded the loss of p210 BCR by more than 24 h. A degraded form of p210 BCR-ABL (about 175 kilodaltons) accounted for the residual autophosphorylation activity seen during the later phases of kinase inactivation following TPA treatment, and this form was preferentially sequestered within BCR-ABL/BCR complexes. This altered BCR-ABL protein, although able to autophosphorylate, had reduced ability to phosphorylate p160 BCR. We conclude that 15 nM TPA treatment of K562 cells initiates effects that simultaneously interfere with the phosphorylation of p160 BCR in BCR-ABL complexes and inactivates the autophosphorylation activity of the full length BCR-ABL protein.(ABSTRACT TRUNCATED AT 250 WORDS)

Cell Differentiation↗
PubMed1998

Arginine butyrate downregulates p210 bcr-abl expression and induces apoptosis in chronic myelogenous leukemia cells.

Downregulation of bcr-abl expression in the chronic myelogenous leukemia cell line K562 using antisense oligonucleotides has been shown to enhance the sensitivity of the cells to apoptotic stimuli, suggesting that p210 bcr-abl, like bcl-2 functions as an anti-apoptosis factor (McGahon A et al, Blood 1994, 83: 1179). In these experiments, the inhibition of p210 bcr-abl expression alone was not sufficient to induce apoptosis. We demonstrated that exposure to low doses (0.5 mM) of a butyric acid analog, arginine butyrate, was capable of inducing apoptosis in selected leukemia cell lines, including K562 cells, and in fresh leukemia cells from patients with chronic myelogenous leukemia. To further explore the mechanisms of this effect, we examined expression of p210 bcr-abl after butyrate exposure and found a dose-related inhibition of p210 bcr-abl protein without concordant change in other phosphoproteins, including the JAK-1 kinase. Further analysis revealed that the inhibition of bcr-abl expression occurs due to transcriptional regulation of the bcr-abl gene by arginine butyrate. These results suggest that arginine butyrate and other butyrate analogs alone or in combination may be useful in the therapy of patients with chronic myelogenous leukemia or bcr-abl expressing acute leukemias.

Antineoplastic Agents↗
PubMed2006

Generation of the BCR/ABL fusion gene in a Philadelphia chromosome-negative chronic myeloid leukaemia: insertion of 5.6 Mb of 9q34 into the BCR region of chromosome 22.

This report describes a chronic myelogenous leukaemia patient with an apparently normal bone marrow karyotype but BCR/ABL fusion-gene-positive. Commercial FISH probes showed an atypical pattern and the BCR/ABL fusion transcript was detected by RT-PCR, but not the reciprocal ABL/BCR. Consecutive FISH assays clarified the mechanism of the masked Ph. The ABL gene and the following 5.6-5.7 Mb of 9q are inserted into the BCR region of chromosome 22. There is no transference of 22q material to chromosome 9 or to any other chromosomes. Clinical features and evolution of the patient are similar to those cases with classic Ph chromosome.

Aged↗
PubMed1996

Genotoxic drugs induce interaction of the c-Abl tyrosine kinase and the tumor suppressor protein p53.

The function of the c-Abl protein tyrosine kinase is unknown. The present studies demonstrate that the antimetabolite 1-beta-D-arabinofuranosylcytosine (ara-C) induces binding of c-Abl and p53. Ara-C treatment of cells that express wild type or a dominant negative, kinase-inactive c-Abl(K-R) was associated with formation of c-Abl-p53 complexes and increased expression of the cyclin-dependent kinase (Cdk) inhibitor p21. However, down-regulation of Cdk2 by ara-C was found in cells expressing wild type c-Abl and not in cells expressing c-Abl(K-R) or those deficient in p53. Similar findings were obtained following treatment of cells with the alkylating agent methyl methanesulfonate (MMS). Cells that express the c-Abl dominant negative or are null for c-Abl exhibited partial abrogation of Cdk2 down-regulation and G1 arrest in response to MMS exposure. Cells lacking the c-abl gene also responded to ara-C and MMS with increases in p53 levels and induction of p21. These findings indicate that the cellular response to certain genotoxic drugs involves binding of c-Abl to p53 and down-regulation of Cdk2 by a c-Abl kinase/p53-dependent mechanism.

Cell Line↗
PubMed1984

Two families of abl-related transcripts in human haematopoietic cells differing in their homology to v-abl.

The transforming gene of the Abelson murine leukaemia virus, v-abl, contains two open reading frames (orf). The 5' orf encodes a tyrosine-specific protein kinase while the 3' orf has the capacity to code for an 18,000 Mr protein. However, no 3' orf product has yet been identified. Using probes capable of distinguishing between the 5' and 3' orfs of v-abl, we have examined the abl-related transcripts present in human haematopoietic cells and leukaemia-derived cell lines, including the chronic myeloid leukaemia-derived cell line K562. Our results indicate that transcripts of 6 kb, 7 kb and 8 kb (kilobase, 10(3) base-pairs) show strong homology to v-abl 5' protein kinase-encoding orf sequences, but are devoid of any sequences from the v-abl 3' orf. In addition, transcripts of 5 kb, 3 kb, 1.6 kb and 1.4 kb, reacting with both 5' orf and 3' orf probes, were observed. The latter species, with coding sequences from both the tyrosine kinase and the putative 18,000 Mr protein, must be transcribed from the human c-abl gene as this is apparently the only human gene containing sequences homologous to the v-abl 3' orf. The 6 kb, 7 kb and 8 kb transcripts may arise either from the c-abl gene through differential splicing, or from one of the three other regions of the human genome with sequences homologous to the 5' orf of v-abl. Examination of genomic DNA from the K562 cell line revealed that the amplification of abl-related sequences, which is presumed to result in the elevated levels of the 8 kb transcript found in this cell line, does not involve sequences homologous to the v-abl 3' orf. This lends credence to the idea that the 8 kb transcript may derive from an abl-related gene other than c-abl. While the significance of the 3' orf of v-abl remains unknown, the data presented strongly suggest the existence of at least two distinct abl-related proteins in human haematopoietic cells.

Abelson murine leukemia virus↗
PubMed1998

Analysis of the gene cluster involved in production and immunity of the peptide antibiotic AS-48 in Enterococcus faecalis.

A region of 7.8 kb of the plasmid pMB2 from Enterococcus faecalis S-48 carrying the information necessary for production and immunity of the peptide antibiotic AS-48 has been cloned and sequenced. It contains the as-48A structural gene plus five open reading frames (as-48B, as-48C, as-48C1, as-48D and as-48D1). Besides As-48D, all the predicted gene products are basic hydrophobic proteins with potential membrane-spanning domains (MSDs). None of them shows any homology with protein sequences stored in databanks, except for As-48D, which shows similarity to the C-terminal domain of ABC transporters and contains a highly conserved ATP-binding site. The gene products of as-48B, as-48C, as-48C1 and as-48D are thought to be involved in AS-48 production and secretion. The only gene able to provide resistance to AS-48 by itself is as-48D1. Immunity also seems to be enhanced at least by the products of as-48B, as-48C1 and as-48D genes. Transcription analysis using probes derived from the different ORFs revealed two large (3.5 and 2.7kb) mRNAs, suggesting that the different genes are organized in two constitutive operons.

Amino Acid Sequence↗
PubMed1997

Biology and treatment of chronic myeloid leukemia.

The BCR-ABL gene rearrangement, the initial event in the development of chronic myeloid leukemia, primarily produces clonal expansion in CML by blocking apoptosis, a genetically programmed process of autonomous cell death. The mechanism by which BCR-ABL blocks apoptosis remains unclear, although recent data are beginning to shed light on the signaling pathway. As with other antiapoptotic signals, BCR-ABL induces cellular resistance to a wide spectrum of cytotoxic antitumor agents. However, apoptosis induced by both cytotoxic T lymphocytes and natural killer or lymphokine-activated killer cells is not blocked by BCR-ABL. A substantial number of patients with chronic myeloid leukemia can now be cured, and the prognosis has improved even for those patients who are not cured. Interferon-alpha has emerged as the treatment of choice for patients who do not undergo an allogeneic bone marrow transplantation. The availability of allogeneic bone marrow transplantation has been increased by the ability to find unrelated donors, although graft-versus-host disease remains a major problem. Adoptive immunotherapy with donor lymphocyte transfusions will induce durable remissions and possibly cures in many patients who relapse after allogeneic BMT. Moreover, a number of investigational approaches, especially autologous BMT, appear promising.

Animals↗
PubMed2000

Ph-negative non-Hodgkin's lymphoma occurring in chronic phase of Ph-positive chronic myelogenous leukemia is defined as a genetically different neoplasm from extramedullary localized blast crisis: report of two cases and review of the literature.

This report describes two cases of Philadelphia chromosome-negative (Ph(-)) non-Hodgkin's lymphomas (NHLs) recognized in patients with chronic phase Ph-positive (Ph(+)) chronic myelogenous leukemia (CML). Lymph node biopsy of patient 1 was initially diagnosed as diffuse large B cell non-Hodgkin's lymphoma (NHL, T cell rich variant), but at relapse showed immunoblastic features with a marked decrease of admixed lymphocyte components. Patient 2 presented with thickened parietal pleura which revealed a CD30-positive anaplastic large cell lymphoma showing null cell phenotype and genotype with abundant admixed neutrophils and lymphocytes. At the time of lymphoma diagnosis, the patients had CML for 33 and 10 months, respectively. DNA obtained from bone marrow cells at the time of lymphoma diagnosis showed BCR/ABL gene rearrangements by both Southern blot analysis and reverse transcription polymerase chain reaction (RT-PCR), but lacked both immunoglobulin and T cell receptor gene rearrangements. BCR gene rearrangement and BCR/ABL fusion gene were also identified in lymph node and pleural biopsies by Southern blot and RT-PCR analysis, respectively. However, both biopsy specimens also contained reactive lymphocytes and neutrophils, and no fusion signals between BCR and ABL genes were identified in the hyperdiploid lymphoma cells of either case by fluorescence in situ hybridization (FISH). These data suggest the lymphoma cells in both cases were not genetically associated with BCR/ABL. Therefore, these cases were not diagnosed as an extramedullary localized blast crisis in CML, but as Ph(-) NHLs. This represents the first definitive demonstration of peripheral B cell lymphoma occurring by a separate genetic pathway, lacking BCR/ABL, in patients with Ph(+) CML. A review of the literature identified two different subtypes of malignant lymphomas arising in patients with an antecedent or concurrent diagnosis of CML. The most common are T cell lymphomas displaying an immature thymic phenotype, while peripheral B cell lymphomas are more rare. Our study shows, however, that 'Ph(+) NHL' occurring in CML or acute lymphocytic leukemia (ALL) may represent an unrelated neoplasm, even if standard cytogenetic analysis reveals a Ph(+) chromosome, and that FISH is required to confirm whether a localized lymphoid neoplasm is either a true extramedullary localized blast crisis or genetically distinct neoplasm. Leukemia(2000) 14, 169-182.

Aged↗
PubMed2001

Allosterically controllable maxizyme-mediated suppression of progression of leukemia in mice.

Chronic myelogenous leukemia (CML) is a hematopoietic malignant disease associated with expression of a chimeric BCR-ABL gene. We recently succeeded in designing a novel allosterically controllable ribozyme, the maxizyme (Tanabe et al. Biomacromolecules 2000, 1, 108-117; Kuwabara et al. Biomacromolecules 2001, 2, 788-799), that not only specifically cleaves BCR-ABL mRNA and induces apoptosis in cultured CML cells but also shows significant inhibition against the growth of an established BV173 cell line in a mouse model (Tanabe et al. Nature 2000, 406, 473-474). As an extension of our studies, we tested the maxizyme against primary CML cells in the same mouse model. The maxizyme under the control of a tRNA(Val) promoter showed significant inhibition against the growth of the primary bone marrow cells from a Japanese patient with CML. Specifically, to examine the applicability of the maxizyme in the treatment of CML, we assessed the antitumor effect of the maxizyme in murine models of CML. Fourteen weeks after the injection of primary CML cells into a NOD-SCID mouse, the bone marrow of the mouse was filled with primary CML cells as a result of diffuse leukemia. In marked contrast, when maxizyme-expressing primary CML cells were injected, the mouse remained disease-free. These results further strengthen our earlier suggestion that the maxizyme technology might provide a useful approach to the treatment of CML.

Allosteric Regulation↗
PubMed2004

Methylation profiles of thirty four promoter-CpG islands and concordant methylation behaviours of sixteen genes that may contribute to carcinogenesis of astrocytoma.

BACKGROUND: Astrocytoma is a common aggressive intracranial tumor and presents a formidable challenge in the clinic. Association of altered DNA methylation patterns of the promoter CpG islands with the expression profile of cancer-related genes, has been found in many human tumors. Therefore, DNA methylation status as such may serve as an epigenetic biomarker for both diagnosis and prognosis of human tumors, including astrocytoma. METHODS: We used the methylation specific PCR in conjunction with sequencing verification to establish the methylation profile of the promoter CpG island of thirty four genes in astrocytoma tissues from fifty three patients (The WHO grading: I: 14, II: 15, III: 12 and IV: 12 cases, respectively). In addition, compatible tissues (normal tissues distant from lesion) from three non-astrocytoma patients were included as the control. RESULTS: Seventeen genes (ABL, APC, APAF1, BRCA1, CSPG2, DAPK1, hMLH1, LKB1, PTEN, p14ARF, p15INK4b, p27KIP1, p57KIP2, RASSF1C, RB1, SURVIVIN, and VHL) displayed a uniformly unmethylated pattern in all the astrocytoma and non-astrocytoma tissues examined. However, the MAGEA1 gene that was inactivated and hypermethylated in non-astrocytoma tissues, was partially demethylated in 24.5% of the astrocytoma tissues (co-existence of the hypermethylated and demethylated alleles). Of the astrocytoma associated hypermethylated genes, the methylation pattern of the CDH13, cyclin a1, DBCCR1, EPO, MYOD1, and p16INK4a genes changed in no more than 5.66% (3/53) of astrocytoma tissues compared to non-astrocytoma controls, while the RASSF1A, p73, AR, MGMT, CDH1, OCT6, MT1A, WT1, and IRF7 genes were more frequently hypermethylated in 69.8%, 47.2%, 41.5%, 35.8%, 32%, 30.2%, 30.2%, 30.2% and 26.4% of astrocytoma tissues, respectively. Demethylation mediated inducible expression of the CDH13, MAGEA1, MGMT, p73 and RASSF1A genes was established in an astrocytoma cell line (U251), demonstrating that expression of these genes is likely regulated by DNA methylation. AR gene hypermethylation was found exclusively in female patients (22/27, 81%, 0/26, 0%, P < 0.001), while the IRF7 gene hypermethylation preferentially occurred in the male counterparts (11/26, 42.3% to 3/27, 11%, P < 0.05). Applying the mathematic method "the Discovery of Association Rules", we have identified groups consisting of up to three genes that more likely display the altered methylation patterns in concert in astrocytoma. CONCLUSIONS: Of the thirty four genes examined, sixteen genes exhibited astrocytoma associated changes in the methylation profile. In addition to the possible pathological significance, the established concordant methylation profiles of the subsets consisting of two to three target genes may provide useful clues to the development of the useful prognostic as well as diagnostic assays for astrocytoma.

Adolescent↗
PubMedDate not supplied

The human met oncogene is related to the tyrosine kinase oncogenes.

The met oncogene was previously isolated from a chemically transformed human cell line, MNNG-HOS. Recent evidence has demonstrated that two classes of transcripts are expressed from the met proto-oncogene locus. The met oncogene, however, expresses an aberrant RNA which has sequences in common with both transcripts. We now report partial nucleotide sequencing of the human met oncogene and show that met is related to the protein kinase oncogenes and growth factor receptors. The met nucleotide sequence is not identical to that of any published gene, and it is more closely homologous to the tyrosine kinases than to the serine/threonine kinases. Within the tyrosine kinase family, the sequenced met domains are most closely related to the human insulin receptor and the viral abl gene. In situ chromosome hybridization has mapped met to human chromosome 7 band 7q21-q31, a location distinct from that of other kinases. This is also a region associated with nonrandom chromosomal deletions observed in a portion of patients with acute nonlymphocytic leukaemia. The accompanying paper shows that this chromosomal locus is also tightly linked with the human heredity disease cystic fibrosis.

Base Sequence↗
PubMed2004

Abl: the prototype of oncogenic fusion proteins.

Since it was first recognized, chronic myeloid leukemia (CML) has always represented a unique model to understand the molecular mechanisms underlying the onset and progression of a leukemic process. CML was the first recognized form of cancer to have a strong association with a recurrent chromosomal abnormality, the t(9;22) translocation, which generates the so-called Philadelphia (Ph)-chromosome. Twenty years later, this abnormality was shown to cover a specific molecular defect, a hybrid BCR-ABL gene, strongly implicated in the pathogenesis of the disease through the production of a protein with a constitutive tyrosine-kinase activity. Although we still lack a complete definition of all the transformation pathways activated by Bcr-Abl, the recent introduction into clinical practice of tyrosine kinase inhibitor represents a major breakthrough to the management of CML and, furthermore, promises to usher in molecularly targeted therapy for other types of leukemia, lymphoma and cancer.

Apoptosis↗
PubMed2005

Genome-based identification of diagnostic molecular markers for human lung carcinomas by PLS-DA.

Partial least squares discriminant analysis (PLS-DA) provides a sound statistical basis for the selection of a limited number of gene transcripts most effective in discriminating different lung tumoral histotypes. The potentialities of the PLS-DA approach are pointed out by its ability to identify genes which, according to current knowledge, are considered molecular markers for colon cancer diagnostics and classification. Indeed application of PLS-DA to in vivo data allowed identification of a set of genes able to discriminate primary lung tumours from colon metastases.

Biomarkers, Tumor↗
PubMed2005

Use of polyclonal rabbit antibodies for detection of the bcr-abl fusion zone in cells transfected with experimental bcr-abl DNA vaccines.

Rabbits were immunized with peptides covering the fusion zone of the chimeric bcr-abl protein in order to prepare antibodies capable of detecting the expression of a selected portion of this fusion zone, by a variety of experimental genetic vaccines. Three peptides of different size covering the b3a2 fusion zone, either unmodified or modified by the omission of alanine at the N-terminal of the a2 section of the fusion zone, and one peptide covering the unmodified b2a2 fusion zone were used. All were capable of eliciting antibodies reactive with the respective immunizing peptides. Their cross-reactivities, especially the results of cross-absorption experiments, strongly suggested that the serum of the rabbit immunized with an octadekapeptide mimicking the b3a2 fusion zone contained antibodies against a novel antigenic determinant created by the chimeric protein, and also against an epitope present in the adjacent a2 section but no antibody reactive with the adjacent b3 region. In Western blotting, these antibodies were capable of detecting the p210bcr-abl or a portion of it (a 25 amino acid-long sequence covering the b3a2 fusion zone) in lysates of 293T cells transfected with plasmids that carried either the full cDNA of the bcr-abl gene or a fragment thereof fused with either the HSP70 gene or certain other genes.

Animals↗
PubMed2000

XRCC3 is required for efficient repair of chromosome breaks by homologous recombination.

XRCC3 was originally identified as a human gene able to complement the DNA damage sensitivity, chromosomal instability and impaired growth of the mutant hamster cell line irs1SF. More recently, it has been cloned, sequenced and found to bear sequence homology to the highly conserved eukaryotic repair and recombination gene RAD51. The phenotype of irs1SF and the identification of XRCC3 as a member of the RAD51 gene family have suggested a role for XRCC3 in repair of DNA damage by homologous recombination. Homologous recombinational repair (HRR) of a specifically induced chromosomal double-strand break (DSB) was assayed in irs1SF cells with and without transient complementation by human XRCC3. Complementation with XRCC3 increased the frequencies of repair by 34- to 260-fold. The results confirm a role for XRCC3 in HRR of DNA DSB, and the importance of this repair pathway for the maintenance of chromosomal integrity in mammalian cells.

Animals↗
PubMed2004

[Therapy of chronic myelogenous leukemia in 2004].

Chronic myelogenous leukemia constitutes a clinical model for other neoplastic diseases. The cytogenetic hallmark of CML, the Ph chromosome with the molecular juxtaposition of BCR and ABL genes and the multistep pathogenesis with the stable chronic phase, the accelerated phase and the terminal blast crisis provide the background for the translation of molecular-cytogenetic findings into clinical practice. The systematic development of the selective BCR-ABL inhibitor imatinib was based on the discovery of the molecular pathogenesis of CML. Promising preclinical data were confirmed in phase I-III trials. Concerning hematologic and cytogenetic response and adverse effects imatinib is superior to interferon alpha. Open questions are treatment duration in patients with good response, long term side effects, persistence of minimal residual disease in almost all patients, development of resistance after long term therapy, and the efficacy of combination treatments. Prospective clinical trials, e. g. CML study IV of the German CML Study Group, should answer these questions. The impact of the various treatment modalities (imatinib, interferon alpha, ara-C, allogeneic stem cell transplantation) will be elucidated. The recruitment of newly diagnosed CML patients into CML-study IV is recommended.

Antineoplastic Agents↗
PubMed1988

Acquired homozygosity of the rearranged bcr allele during the acute leukemic phase of a patient with Ph-negative chronic myeloid leukemia.

A 45-year-old male patient with Ph-negative chronic myeloid leukemia (CML) had rearranged bcr-3' and bcr-5' gene regions in Southern blot studies when leukemia was diagnosed. During development of terminal blast crisis, successive blood samples showed a progressive decrease in the amount of germline bcr DNA and its complete loss by full blast crisis. There were also increased amounts of rearranged bcr DNA consistent with acquired homozygosity. A similar result was obtained with an IgV lambda probe and indicated homozygosity of a significant part of chromosome 22. The bcr-abl gene complex behaves as a somatic dominant in CML, and we suggest that its acquired homozygosity is a mechanism of bcr-abl amplification similar to duplication of the Ph chromosome commonly found in the blast crisis of CML.

Alleles↗