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PubMed2006

The tyrosine kinase c-Abl protects c-Jun from ubiquitination-mediated degradation in T cells.

The cross-talk of ubiquitination with other types of posttranscriptional modifications, such as phosphorylation, regulates the stability of many proteins. We have previously demonstrated that c-Jun is a substrate of Itch, a HECT-type E3 ubiquitin ligase. c-Jun is also a substrate of the tyrosine kinase c-Abl. Here we report that genetic ablation of c-Abl accelerated c-Jun degradation. Phosphorylation of the tyrosine within the PPXY motif by c-Abl inhibited c-Jun ubiquitination and its binding by Itch. The nuclear localization of c-Abl, triggered by T-cell activation signals, was essential for its activity in regulating c-Jun transcription activity. These findings define a potential molecular mechanism for the immunodeficiency in mice lacking the c-abl gene.

Animals↗
PubMed1991

A possible correlation between the type of bcr-abl hybrid messenger RNA and platelet count in Philadelphia-positive chronic myelogenous leukemia.

The Philadelphia (Ph1) chromosome, in which the hybrid bcr-abl gene is formed, is thought to be the initial event in chronic myelogenous leukemia (CML). The position of the breakpoint within the breakpoint cluster region (bcr) on Ph1 chromosome and the splicing pattern determine the species of the fused bcr-abl messenger RNA (mRNA). We tried to detect the two types of fused mRNAs in 57 chronic-phase cases of Ph1-positive CML using the polymerase chain reaction procedure (RT-PCR). The bcr exon 2/abl exon 2 fused mRNA (b2-a2) was detected in 17 patients, the bcr exon 3/abl exon 2 fused mRNA (b3-a2) was detected in 34 patients, and both types of mRNA were detected in six patients. The platelet counts of patients who expressed b3-a2 mRNA or both types were significantly higher than those of patients who expressed only b2-a2 (841.5 v 373.5 x 10(9)/L; P less than .015), although there was no significant difference in the white blood cell counts or hemoglobin. This finding suggests a possibility that the type of bcr-abl mRNA may affect the thrombopoietic activity in CML.

Base Sequence↗
PubMed2004

Gene therapy for chronic peripheral arterial disease: what role for the vascular surgeon?

The incidence of peripheral arterial disease is rising and despite advances in clinical management, many problems remain unsolved. Better knowledge of the mechanisms and consequences associated with chronic muscle ischemia has opened the way for development of new treatment strategies, including therapeutic angiogenesis. Therapeutic angiogenesis is a promising technique based on experimental studies showing that growth factors or genes able to increase capillary density can be used to reduce the impact of muscle ischemia and increase blood flow to ischemic tissue. Enthusiasm for this technique has prompted numerous clinical trials with encouraging results, but data are still inconclusive. Optimal indications for gene therapy must be defined and further experimental progress is needed to respond to ethical issues. Therapeutic angiogenesis should be viewed as an adjunct to rather than as a competitor of current surgical revascularization techniques.

Chronic Disease↗
PubMed1988

A cytogenetic and molecular analysis of five variant Philadelphia translocations in chronic myeloid leukemia.

Three patients had complex translocations involving 9q34, 22q11, and a third chromosome (Xq11, 7q11.2, or 15q11.2). Two patients had apparently simple variant Philadelphia (Ph) translocations, t(19;22) and t(11;22), with no obvious involvement of chromosome 9, and the Ph was masked in the t(11;22). In situ hybridization studies showed transposition of the abl gene from chromosome 9q34 to the breakpoint cluster region (bcr) of chromosome 22 in all five patients; this was confirmed by rearrangements of the bcr gene in leukemic DNA. In situ hybridization also showed that the bcr-3' and c-sis probes consistently translocated to recipient chromosomes X, 1, 7, 11, and 15, whereas IgC lambda remained on chromosome 22q. These results confirm that association of abl and bcr is a consistent feature of chronic myeloid leukemia irrespective of the cytogenetic presentation and support the conclusion of Hagemeijer that all simple variant Ph translocations are, in fact, complex and involve at least three chromosomes.

Adult↗
PubMed2001

Rituximab can be useful as treatment for minimal residual disease in bcr-abl-positive acute lymphoblastic leukemia.

We report the results of administering CD20 monoclonal antibody (MoAb) in a 32-year-old man with bcr-abl-positive acute lymphoblastic leukemia. Morphological complete remission was achieved after two lines of chemotherapy with persistence of blast cells (2%) in flow cytometric analysis of marrow cells. Since no HLA-matched donor for allogeneic bone marrow transplantation (BMT) was found, anti-CD20 MoAb therapy was administered for in vivo marrow purging, prior to autologous peripheral blood stem cell (PBSC) harvest and transplantation. After MoAb therapy <0.1% of blast cells were observed and the molecular abnormality (bcr-abl gene rearrangement) disappeared.

Adult↗
PubMedDate not supplied

Glivec and CML: a lucky date.

Chronic Myeloid Leukemia (CML) has always been an ideal model to understand the molecular pathogenesis of human leukaemias and the way to cure them. This can be ascribed to the fact that CML was the first human cancer demonstrated to be strongly associated to the presence of a recurrent chromosomal translocation (the t(9;22)(q34;q11) that creates the Philadelphia (Ph)-chromosome) and to a specific molecular defect, the formation of a hybrid BCR-ABL gene that generates new fusion proteins endowed with a constitutive tyrosine-kinase (TK) activity, strongly implicated in the pathogenesis of the disease. The introduction into clinical practice of imatinib, (Glivec, Gleevec, Novartis), a potent tyrosine kinase inhibitor of the Bcr-Abl protein as well as of a restricted number of other TKs, has not only produced a substantial improvement in the treatment of CML, but represents a major break-through in the perspective of opening a new era, that of molecularly targeted therapy, in the management of other types of leukemia, lymphoma and cancer in general.

Antineoplastic Agents↗
PubMed1990

Transposition of the abl proto-oncogene in Philadelphia--negative chronic myeloid leukaemia and acute lymphocytic leukaemia.

Transposition of the abl gene was demonstrated in seven Philadelphia (Ph'-) negative patients with either chronic myeloid leukaemia (CML) or acute lymphocytic leukaemia (ALL) by chromosomal in situ hybridization. In six out of seven CML patients and one out of two ALL patients, a significant accumulation of abl hybridization grains was localized to chromosome 22. Hybridization with both abl and sis resulted in the consistent formation of double hybridization events on chromosome 22. Transposition of abl was not apparent in one patient with Ph'-negative CML and in one patient with Ph'-negative ALL. The data suggest that transposition of abl to chromosome 22 is a feature of a particular subgroup of Ph'-negative leukaemias.

Chromosome Mapping↗
PubMed2001

Quantitative monitoring of the PRAME gene for the detection of minimal residual disease in leukaemia.

PRAME (Preferentially expressed antigen of melanoma) has been previously identified as a melanoma antigen recognized by cytotoxic T cells (CTLs) and found to be expressed in a variety of cancer cells including leukaemic cells. We have screened 98 Japanese patients with leukaemia and lymphoma for expression of the PRAME gene using semiquantitative reverse transcription polymerase chain reaction (RT-PCR). Forty-one patients (42%) showed high levels of PRAME expression. Eight of these patients were then monitored using real-time PCR for a period of 10-37 months. Significant reductions in the PRAME expression were observed in all patients after chemotherapy. An increased expression was detected in the two patients who relapsed, one of which was before cytological diagnosis. These changes were correlated with those of other known genetic markers, such as the bcr-abl gene. Therefore, quantitative monitoring of the PRAME gene using real-time PCR method may be useful for detecting minimal residual disease and to predict subsequent relapse, especially in patients without known genetic markers. In addition, a PRAME-positive leukaemia cell line and fresh leukaemic cells were found to be susceptible to lysis by PRAME-specific CTLs established from a patient with melanoma, suggesting that the PRAME peptide can also be a target leukaemia antigen for T cells.

Adult↗
PubMed2000

Complex chromosome rearrangements may locate the bcr/abl fusion gene sites other than 22q11.

BACKGROUND AND OBJECTIVE: From 5-8% of Philadelphia (Ph) positive patients with chronic myeloid leukemia (CML) show variant translocations in which at least a third chromosome in addition to 9q34 and 22q11 is involved. The formation mechanisms and clinical significance of variant Ph translocations are still unclear. The BCR/ABL chimeric gene encoding for chimeric proteins is always present and maps on the 22q- regardless of the type of translocation. We studied two apparently Ph negative CML patients with unusual karyotypes both showing a typical b3a2 rearrangement. DESIGN AND METHODS: Dual-color fluorescence in situ hybridization (FISH) can visualize BCR and ABL genes and localize the BCR/ABL fusion gene. We used FISH to study the formation mechanisms of variant Ph translocations in two patients. RESULTS: The chimeric BCR/ABL gene was located on a locus other than the expected 22q11 in both patients. In the first case the fusion signal was present on the 9q34 band whereas in the second patient it was detected on chromosome 8, involved in masked Ph formation. INTERPRETATION AND CONCLUSIONS: The location of the hybrid BCR/ABL gene on chromosomes other than 22q- is a rare event which can only be observed using the FISH technique. When these unusual translocations occur the hypothesis most often put forward is that several consecutive cytogenetic events have taken place. The factors which regulate the formation of these breakpoints have yet to be clarified. The FISH technique allows the identification of chromosome rearrangements that could not otherwise be detected by conventional banding procedures. The location of the hybrid BCR/ABL gene on sites other than 22q11 represents a rare type of variant Ph translocation. The real frequency and clinical significance of such rearrangements need to be investigated.

Aged↗
PubMed2002

Transferable tetracycline resistance in Listeria monocytogenes from food in Italy.

Mechanisms of tetracycline resistance were investigated in two recent Listeria monocytogenes isolates from food, with L. innocua 52P tet(r) as a control. Tetracycline resistance was transferred conjugatively from all three strains to L. ivanovii and from one isolate and the control to Enterococcus faecalis. Molecular analysis demonstrated a chromosomal location for the tet determinant, which was identified as tetM in all cases. These studies are the first to show that L. monocytogenes from food could be a source of tetracycline resistance genes able to spread to other micro-organisms.

Blotting, Southern↗
PubMed1982

Abelson murine leukemia virus: structural requirements for transforming gene function.

The integrated Abelson murine leukemia virus (A-MuLV) genome cloned in bacteriophage lambda gtWES.lambda B was used to localize viral genetic sequences required for transformation. Comparison of the biological activity of cloned A-MuLV genomic and subgenomic fragments showed that subgenomic clones that lacked the 5' long terminal repeat and adjoining sequences (300 base pairs downstream of the repeat) were not biologically active. In contrast, subgenomic clones that lacked the 3' long terminal repeat and as much as 1.3 kilobase pairs of the A-MuLV cell-derived abl gene were as efficient as wild-type viral DNA in transformation. The A-MuLV-encoded polyprotein P120 and its associated protein kinase activity were detected in transformants obtained by transfection with Cla I, BamHI, and HindIII subgenomic clones. In contrast, individual transformants obtained with subgenomic Sal I clones expressed A-MuLV proteins ranging in size from 82,000 to 95,000 daltons. Each demonstrated an associated protein kinase activity. These results provide direct genetic evidence that only the proximal 40% of abl with its associated 5' helper viral sequences is required for fibroblast transformation.

Abelson murine leukemia virus↗
PubMed2005

AMN107: tightening the grip of imatinib.

The Abl inhibitor imatinib is a highly effective therapy for patients with chronic myeloid leukemia. Relapses are relatively uncommon in newly diagnosed patients, but are the rule in patients with more advanced disease. Mutations in the BCR-ABL gene are the most common cause of relapse. Working from the imatinib chemical structure, a higher-affinity family member, AMN107, was designed. AMN107 is approximately 20-fold more potent than imatinib, and this translates into improved inhibitory activity against most of the common BCR-ABL mutations. The implications of these results, and the potential role this and other novel ABL inhibitors may have in treating patients with CML, are discussed.

Animals↗
PubMed2006

Deletion size characterization of der(9) deletions in Philadelphia-positive chronic myeloid leukemia.

About 95% of the CML patients with chronic myeloid leukemia (CML) have a Philadelphia chromosome resulting from a reciprocal translocation between bands 9q34 and 22q11.2 that juxtaposes the 3' region of the ABL gene to the 5' region of BCR. Over the past few years, submicroscopic deletions due to the loss of sequences proximal to chromosome 9 breakpoint or distal to chromosome 22 breakpoint have been found using fluorescence in situ hybridization (FISH). Among 150 CML bone marrow samples analyzed by molecular cytogenetics in our laboratory, 11 had a der(9) deletion detectable by FISH (deletion of the 5'ABL region and 3'BCR region in 10 samples and deletion of the 5'ABL region solely in 1 sample). To delineate the size of the deletions, FISH mapping was performed using 22 bacterial artificial chromosomes (BACs), 11 on either side of the breakpoints, the mean distance between BACs being 0.5 Mb. The deletion size of the 5'ABL region on the der(9) extended from 2 to 5 Mb, the minimal deletion size being localized between BACs RP11-101E3 and RP11-83J21. In two patients, the deletion size of the 3'BCR region was about 500 kb (between RP11-80O7 and RP11-681C06). The poor prognosis associated with these deletions was postulated by several workers to be explained by haploinsufficiency of a tumor suppressor gene. However, in our cases, the hypothetical deletion of one or more tumor suppressor genes is not sufficient to explain the poor response to interferon therapy, but the good response to imatinib treatment. We think that there could be one or more genes coding for interferon receptors or for proteins acting directly or indirectly with these receptors in the deleted regions.

Chromosomes, Artificial, Bacterial↗
PubMed1987

Molecular characterization of the testis specific c-abl mRNA in mouse.

The c-abl gene encodes a protein tyrosine kinase and is transcribed from at least two promoters giving rise to transcripts of two size classes of approximately 5 and 6 kb in length. These mRNAs only differ in their most 5' exon and encode proteins of similar size but with different N-termini. In the mouse testis an additional abundant c-abl mRNA of 4 kb is detected. This mRNA was shown to be expressed in the haploid male germ cells of the adult mouse. Here we describe the cloning and molecular characterization of a cDNA representing the testis specific c-abl transcript. We show that the 4 kb c-abl mRNA arises from alternative polyadenylation of an RNA transcribed from the same promoter as the 5 kb mRNA. The site of polyadenylation is unusual in this shorter transcript as it is not preceded by the highly conserved hexanucleotide AAUAAA. The use of this polyadenylation site removes 1.2 kb of 3' sequences present in the somatic c-abl mRNAs, but does not affect the main open reading frame of the transcript. Using in situ hybridization on whole testis sections it is shown that the 4 kb c-abl mRNA is most abundant in the elongating spermatids.

Animals↗
PubMed1987

Mapping of four distinct BCR-related loci to chromosome region 22q11: order of BCR loci relative to chronic myelogenous leukemia and acute lymphoblastic leukemia breakpoints.

A probe derived from the 3' region of the BCR gene (breakpoint cluster region gene) detects four distinct loci in the human genome. One of the loci corresponds to the complete BCR gene, whereas the others contain a 3' segment of the gene. After HindIII cleavage of human DNA, these four loci are detected as 23-, 19-, 13-, and 9-kilobase-pair fragments, designated BCR4, BCR3, BCR2, and BCR1, respectively, with BCR1 deriving from the original complete BCR gene. All four BCR loci segregate 100% concordantly with human chromosome 22 in a rodent-human somatic cell hybrid panel and are located at chromosome region 22q11.2 by chromosomal in situ hybridization. The BCR2 and BCR4 loci are amplified in leukemia cell line K562 cells, indicating that they fall within the amplification unit that includes immunoglobulin lambda light chain locus (IGL) and ABL locus on the K562 Philadelphia chromosome (Ph1); additionally, in chronic myelogenous leukemia-derived mouse-human hybrids retaining a Ph1 chromosome in the absence of the 9q+ and normal chromosome 22, BCR2 and BCR4 loci are retained, whereas the 3' region of BCR1 and the BCR3 locus are lost, indicating that BCR3 is distal to BCR1 on chromosome 22. Similarly, in mouse-human hybrids retaining a Ph1 chromosome derived from an acute lymphoblastic leukemia-in the absence of the 9q+ and 22, only BCR2 and BCR4 loci are retained, indicating that the breakpoint in this acute lymphoblastic leukemia, as in chronic myelogenous leukemia, is proximal to the BCR1 3' region, but distal to the IGLC locus and the BCR2 and BCR4 3' loci. Thus, the order of loci on chromosome 22 is centromere----BCR2, BCR4, and IGL----BCR1----BCR3----SIS, possibly eliminating BCR2 and BCR4 loci as candidate targets for juxtaposition to the ABL gene in the acute lymphoblastic leukemia Ph1 chromosome.

Chromosome Aberrations↗
PubMed1991

[DNA diagnosis of human cancers: lymphoid malignancies and leukemia].

Usefulness of DNA analysis in diagnosis of hematopoietic malignancy was discussed. Examination on the presence of rearrangement in immunoglobulin (Ig) and T cell receptor (TCR) was the first DNA analysis used for clinical diagnosis of lymphoid malignancy to determine the cell-lineage and clonality of proliferating lymphoid cells. One point mutation in ras oncogene has also been used to detect residual leukemic cells as well as diagnosis of the early relapse of leukemia, although not all leukemic cells have this mutation. Presence of BCR-abl fused gene is a genetic marker for Ph1 chromosome. Analysis of BCR-abl gene has made it possible to diagnose the Ph1 ALL and masked Ph1 CML. Development of PCR technique markedly increased the possibility for the use of DNA analysis in clinical medicine. In addition to Ph1 chromosome, various chromosomal abnormalities resulted in a reciprocal translocation between Ig or TCR gene and other genes in various lymphoid malignancies, such as Burkitt lymphoma and follicular lymphoma. These translocations can be analyzed by Southern hybridization and used for clinical diagnosis.

Chromosome Fragility↗
PubMed1995

Human and other mammalian genomes contain transposons of the mariner family.

Internal fragments of the putative transposase gene of mariner-like elements (MLEs) were amplified from human, mouse, rat, chinese hamster, sheep and bovine genomic DNAs by polymerase chain reaction (PCR). The sequences identified in human, ovine and bovine genomes correspond to ancient degenerate transposons. Screening mammalian sequence libraries identified a truncated element in the human ABL gene and the sequence of its 5'-ITR was determined. This ITR sequences were used in PCR experiments with DNA from six mammalian species and detected full-sized and deleted MLEs. The presence of MLE in mammalian genomes demonstrates that they are ubiquitous mobile elements found from fungi to man. This observation strongly raises the possibility that MLE could constitute tools for the modification of eucaryotic genomes.

Amino Acid Sequence↗
PubMed2003

Mechanisms of autoinhibition and STI-571/imatinib resistance revealed by mutagenesis of BCR-ABL.

The Bcr-Abl fusion protein kinase causes chronic myeloid leukemia and is targeted by the signal transduction inhibitor STI-571/Gleevec/imatinib (STI-571). Sequencing of the BCR-ABL gene in patients who have relapsed after STI-571 chemotherapy has revealed a limited set of kinase domain mutations that mediate drug resistance. To obtain a more comprehensive survey of the amino acid substitutions that confer STI-571 resistance, we performed an in vitro screen of randomly mutagenized BCR-ABL and recovered all of the major mutations previously identified in patients and numerous others that illuminate novel mechanisms of acquired drug resistance. Structural modeling implies that a novel class of variants acts allosterically to destabilize the autoinhibited conformation of the ABL kinase to which STI-571 preferentially binds. This screening strategy is a paradigm applicable to a growing list of target-directed anti-cancer agents and provides a means of anticipating the drug-resistant amino acid substitutions that are likely to be clinically problematic.

Amino Acid Sequence↗