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PubMed2005

c-Abl is required for staurosporine-induced caspase activity.

Caspases are the intracellular molecular machinery responsible for apoptotic cell death. The regulation of these critical proteolytic enzymes is known to occur on multiple levels. While their expression as inactive precursors exhibits a primary level of control, other types of regulation such as post-translational modifications also play a role. Nuclear c-Abl, a nonreceptor tyrosine kinase, plays a role in the regulation of apoptosis in response to DNA damage. The function of cytoplasmic c-Abl in cell death is not fully understood. Here, we report c-Abl dependent caspase-3 and caspase-8 activity in response to staurosporine. Despite the presence and apparent activation of the mitochondrial-dependent apoptotic pathway and cellular demise, we find no caspase-3 activity in cells lacking the Abl gene (Abl(-/-)). These findings demonstrate a novel tyrosine kinase dependent regulation of caspase-mediated cell death.

Animals↗
PubMed2004

Adhesion-dependent regulation of p190RhoGAP in the developing brain by the Abl-related gene tyrosine kinase.

Abl family kinases, which include the mammalian Abl and Arg (Abl-related gene) kinases, regulate neuronal morphogenesis in developing metazoa (for review, see [1]). Activation of Abl kinase activity directs changes in actin-dependent processes such as membrane ruffling, filopodial protrusion, and cell motility. However, the mechanisms by which increased Abl or Arg kinase activity promote cytoskeletal rearrangements are unclear. We provide evidence that the Rho inhibitor p190RhoGAP (GTPase-activating protein) is an Arg substrate in the postnatal mouse brain. We show that p190RhoGAP has reduced phosphotyrosine content in postnatal arg(-/-) mouse brain extracts relative to wild-type extracts. In addition, the adhesion-dependent stimulation of p190RhoGAP phosphorylation observed in wild-type cells is not observed in arg(-/-) fibroblasts and neurons. Arg can phosphorylate p190RhoGAP in vitro and in vivo on tyrosine (Y) 1105. We find that Arg can stimulate p190RhoGAP to inhibit Rho and that Arg-mediated phosphorylation is required for this stimulation. Phosphorylation by Arg also promotes p190RhoGAP's association with p120RasGAP and stimulates p190RhoGAP's ability to induce neuritogenesis in neuroblastoma cells. Our results demonstrate that p190RhoGAP is an Arg substrate in the developing brain and suggest that Arg mediates the adhesion-dependent regulation of neuronal morphogenesis in the postnatal brain by phosphorylating p190RhoGAP.

3T3 Cells↗
PubMed1988

DNA sequence, structure, and tyrosine kinase activity of the Drosophila melanogaster Abelson proto-oncogene homolog.

We report our molecular characterization of the Drosophila melanogaster Abelson gene (abl), a gene in which recessive loss-of-function mutations result in lethality at the pupal stage of development. This essential gene consists of 10 exons extending over 26 kilobase pairs of genomic DNA. The DNA sequence encodes a protein of 1,520 amino acids with strong sequence similarity to the human c-abl proto-oncogene beginning in the type lb 5' exon and extending through the region essential for tyrosine kinase activity. When the tyrosine kinase homologous region was expressed in Escherichia coli, phosphorylation of proteins on tyrosine residues was observed with an antiphosphotyrosine antibody. These results show that the abl gene is highly conserved through evolution and encodes a functional tyrosine protein kinase required for Drosophila development.

Amino Acid Sequence↗
PubMed1985

Activation of the c-abl oncogene by viral transduction or chromosomal translocation generates altered c-abl proteins with similar in vitro kinase properties.

The v-abl protein of Abelson murine leukemia virus is a tyrosine-specific kinase. Its normal cellular homolog, murine c-abl, does not possess detectable tyrosine kinase activity in vitro. Previously, we have detected tyrosine kinase activity in vitro for an altered c-abl gene product (c-abl P210) in the K562 human chronic myelogenous leukemia cell line. The expression of this variant c-abl gene product correlates with chromosomal translocation and amplification of the c-abl gene in K562 cells. Like v-abl, c-abl P210 is a fusion protein containing non-abl sequences near the amino terminus of c-abl. We compared the in vitro tyrosine kinase activity of c-abl P210 with that of wild-type murine v-abl. The remarkable similarities of these two proteins with respect to cis-acting autophosphorylation, trans-acting phosphorylation of exogenous substrates, and kinase inhibition, using site-directed abl-specific antisera, suggested that c-abl P210 could function similarly to v-abl in vivo. In addition, c-abl P210 possessed an associated serine kinase activity in immunoprecipitates. The serine kinase activity was not inhibited by site-directed, abl-specific antisera that inhibit the tyrosine kinase activity, suggesting that the serine kinase activity is not an intrinsic property of c-abl P210. Thus, the activation of the c-abl gene in a human leukemia cell line may have functional consequences analogous to activation of the c-abl gene in Abelson murine leukemia virus.

Abelson murine leukemia virus↗
PubMed1994

Detection of BCR-ABL fusion genes in adult acute lymphoblastic leukemia by the polymerase chain reaction.

The sensitivity and clinical utility of the polymerase chain reaction (PCR) assay for the detection of BCR-ABL gene rearrangement was compared to conventional cytogenetics for the Philadelphia chromosome (Ph1) in adult acute lymphoblastic leukemia (ALL) patients entered onto a single clinical trial. Ninety-three patients had evaluable PCR assays for both the p190bcr-abl and p210bcr-abl type of BCR-ABL gene rearrangements. Twenty-one of 93 patients (23%) were positive for the BCR-ABL rearrangement by the PCR assay. Fourteen of these patients had the p210brc-abl BCR-ABL rearrangement characteristically seen in CML patients, while seven had the p190bcr-abl rearrangement seen in ALL alone. Of 61 patients analyzed, both with conventional cytogenetics and PCR, eight (13%) were positive for the Ph1, while 14 (23%) were positive for the BCR-ABL rearrangement by the PCR assay. Discordance between the PCR assay and cytogenetics occurred in eight cases where the PCR assay was positive and the cytogenetics negative, and two cases where the PCR assay was negative and cytogenetics positive. PCR positivity did not correlate with treatment response, survival, or relapse-free survival, but there was a higher percentage of L2 FAB morphology in the PCR+ cases compared to the PCR-cases (67 vs. 28%, p = 0.003). In addition, the data suggested that patients with a p190bcr-abl rearrangement have a better response to induction therapy, but a worse relapse-free survival compared to patients with a p210bcr-abl breakpoint, but these differences were not statistically significant. These data suggest that PCR and conventional cytogenetics may provide complementary information, since there appear to be a subset of patients who are Ph1-negative yet BCR-ABL positive by PCR. Further studies will be required to determine the prognostic significance of the detailed information about BCR-ABL breakpoints that is available from the PCR assay.

Adolescent↗
PubMed1993

Expression of the ABL-BCR fusion gene in Philadelphia-positive acute lymphoblastic leukemia.

We have previously shown that the chimeric gene ABL-BCR, formed on the derivative chromosome 9q+ as a result of the t(9;22) translocation, is transcriptionally active in 65% of chronic myeloid leukemia patients. We have now used the same technique, reverse transcription/polymerase chain reaction amplification of ABL-BCR transcripts, to study nine patients with Philadelphia (Ph) chromosome-positive acute lymphoblastic leukemia (ALL); seven expressed the P190 and two the P210 type of BCR-ABL fusion protein. All seven patients with P190 had ABL-BCR transcripts containing a junction between ABL exon Ib and BCR exon 2 (Ib-e2); in two cases, ABL-BCR transcripts with the Ia-e2 junction type were also present. Of the two P210 ALL patients, one had a Ib-b4 ABL-BCR transcript and the other showed no detectable ABL-BCR expression. Although the BCR-ABL gene is probably fundamental in the pathogenesis of the Ph+ leukemias, differential expression of the ABL-BCR gene could contribute to the biologic heterogeneity of the disease.

Adult↗
PubMed2004

Synthesis of N3- and 2-NH2-substituted 6,7-diphenylpterins and their use as intermediates for the preparation of oligonucleotide conjugates designed to target photooxidative damage on single-stranded DNA representing the bcr-abl chimeric gene.

Two 17-mer oligodeoxynucleotide-5'-linked-(6,7-diphenylpterin) conjugates, 2 and 3, were prepared as photosensitisers for targeting photooxidative damage to a 34-mer DNA oligodeoxynucleotide (ODN) fragment 1 representing the chimeric bcr-abl gene that is implicated in the pathogenesis of chronic myeloid leukaemia (CML). The base sequence in the 17-mer was 3'G G T A G T T A T T C C T T C T T5'. In the first of these ODN conjugates (2) the pterin was attached at its N3 atom, via a -(CH2)3OPO(OH)- linker, to the 5'-OH group of the ODN. Conjugate 2 was prepared from 2-amino-3-(3-hydroxypropyl)-6,7-diphenyl-4(3H)-pteridinone 10, using phosphoramidite methodology. Starting material 10 was prepared from 5-amino-7-methylthiofurazano[3,4-d]pyrimidine 4 via an unusual highly resonance stabilised cation 8, incorporating the rare 2H,6H-pyrimido[6,1-b][1,3]oxazine ring system. In the characterisation of 10 two pteridine phosphazenes, 15 and 29, were obtained, as well as new products containing two uncommon tricyclic ring systems, namely pyrimido[2,1-b]pteridine (20 and 24) and pyrimido[1,2-c]pteridine (27). In the second ODN conjugate the linker was -(CH2)5CONH(CH2)6OPO(OH)- and was attached to the 2-amino group of the pterin. In the preparation of 3, the N-hydroxysuccinimide ester 37 of 2-(5-carboxypentylamino)-6,7-diphenyl-4(3H)-pteridinone was condensed with the hexylamino-modified 17-mer. Excitation of 36 with near UV light in the presence of the single-stranded target 34-mer, 5'T G A C C A T C A A T A A G14 G A A G18 A A G21 C C C T T C A G C G G C C3' 1 caused oxidative damage at guanine bases, leading to alkali-labile sites which were monitored by polyacrylamide gel electrophoresis. Cleavage was observed at all guanine sites with a marked preference for cleavage at G14. In contrast, excitation of ODN-pteridine conjugate 2 in the presence of 1 caused oxidation of the latter predominantly at G18, with a smaller extent of cleavage at G15 and G14 (in the double-stranded portion) and G21. These results contrast with our previous observation of specific cleavage at G21 with ruthenium polypyridyl sensitisers, and suggest that a different mechanism, probably one involving Type 1 photochemical electron transfer, is operative. Much lower yields were found with the ODN-pteridine conjugate 3, perhaps as a consequence of the longer linker between the ODN and the pteridine in this case.

Base Pairing↗
PubMed1992

Clinical significance of the BCR-ABL fusion gene in adult acute lymphoblastic leukemia: a Cancer and Leukemia Group B Study (8762).

The Philadelphia (Ph1) chromosome, or its molecular counterpart, the BCR-ABL fusion gene, is a rare but important prognostic indicator in childhood acute lymphoblastic leukemia (ALL), but its impact on adult ALL has not been well ascertained. A prospective study of the BCR-ABL fusion gene was begun on patients entered on clinical trials conducted by the Cancer and Leukemia Group B (CALGB). All patients received intensive, multiagent chemotherapy that included daunorubicin. Over 2 years, 56 patients were studied for molecular evidence of a BCR-ABL gene using Southern blot and pulsed-field gel hybridization analysis. Results were compared with cytogenetic detection of a Ph1 chromosome, and clinical features were compared for the BCR-ABL-positive and -negative groups. Molecular methods detected the BCR-ABL gene in 30% of cases compared with cytogenetic detection of the Ph1 chromosome in only 23%. The majority of cases (76%) showed the p190 gene subtype similar to pediatric ALL; the BCR-ABL-positive cases displayed a more homogeneous immunophenotype than the BCR-ABL-negative cases and were predominantly CALLA positive (86%) and B-cell surface antigen positive (82%). The rate of achieving complete remission was similar in the BCR-ABL-positive and -negative groups (71% and 77%, respectively, P = .72). There were more early relapses in the BCR-ABL-positive group, resulting in a shorter remission duration that was especially marked in the CALLA-positive and B-cell antigen-positive populations. These preliminary data suggest that the impact of the BCR-ABL gene on clinical outcome in ALL may be on maintenance of complete remission (CR) rather than achievement of CR when aggressive, multiagent chemotherapy is used. This study identifies the BCR-ABL gene as an important factor in adult ALL and demonstrates the utility of molecular methods for its accurate diagnosis.

Adolescent↗
PubMed1984

The mouse c-abl locus: molecular cloning and characterization.

The mouse c-abl gene, part of the sequence of which was captured in Moloney murine leukemia virus to generate the transforming gene (v-abl) of the Abelson murine leukemia virus, has been isolated and characterized. The c-abl locus spans 40 kb in the mouse genome with the v-abl homologies distributed in no less than ten clusters along 25 kb of the cloned DNA. Partial sequence of the v-abl homologous regions indicates that v-abl derived from c-abl mainly by splicing of multiple exons of the c-abl gene. The c-abl sequences can be subdivided into two regions: a tyrosine kinase coding sequence distributed among eight small clusters on the 5' end of the gene and a C-terminal portion consisting of one small and one large cluster, which are needed neither for the tyrosine kinase activity nor for the transforming ability of v-abl. Apparent exon/intron boundaries in the homologous kinase-coding regions of c-abl and c-src are at different locations.

Amino Acid Sequence↗
PubMed2003

Double minutes containing amplified bcr-abl fusion gene in a case of chronic myeloid leukemia treated by imatinib.

Amplification of the bcr-abl fusion gene has recently been associated with resistance to imatinib therapy in chronic myeloid leukemia (CML). A 55-yr-old man was diagnosed with Philadelphia (Ph) chromosome-positive CML. Resistance to interferon treatment and occurrence of blastic phase lead to the decision of imatinib therapy. After two autologous stem cell transplantation, the patient reverted to chronic phase with a decrease in the proportion of Ph chromosome-positive cells under imatinib. A second blastic phase occurred 4 months after transplantation, of which the patient died. Cytogenetic studies, including fluorescent in situ hybridization, showed a (9;22)(q34;q11) translocation and one bcr-abl fusion gene during the whole evolution, but for the last 2 months. Bcr-abl gene amplification (over 25 copies) was noted while banding cytogenetics showed a karyotype of 55-62 chromosomes with multiple double minutes (dmin). To the best of our knowledge, dmin containing amplified bcr-abl gene has never been reported in patients with CML. Therefore, although we cannot exclude that the gene amplification was strictly associated with disease progression, our data may suggest that the amplification resulted in resistance to imatinib.

Aneuploidy↗
PubMed2002

Targeting of photooxidative damage on single-stranded DNA representing the bcr-abl chimeric gene using oligonucleotide-conjugates containing [Ru(phen)3](2+)-like photosensitiser groups.

Photooxidative damage was induced predominantly at a single guanine base in a target DNA by irradiation (lambda > 330 nm) in the presence of complementary oligodeoxynucleotide conjugates (ODN-5'-linker-[Ru(phen)3]2+) (phen = 1,10-phenanthroline). The target DNA represents the b2a2 variant of the chimeric bcr-abl gene implicated in the pathogenesis of chronic myeloid leukaemia, and the sequence of the 17mer ODN component of the conjugate (3' G G T A G T T A T T C C T T C T T 5') was complementary to the junction region of the sense strand sequence of this oncogene. Two different conjugates were prepared, both of them by reaction of the appropriate succinimide ester with 5'-hexylamino-derivatised 17mer ODN. In Ru-ODN-1 (7) the linker was -(CH2)6-NHCO-bpyMe (-bpyMe = 4'-[4-methyl-2,2'-bipyridyl]), whereas in Ru-ODN-2 (13) it was -(CH2)6-NHCO-(CH2)3-CONH-phen. Photoexcitation of either of the conjugates when hybridised with the 32P-5'-end-labelled target 34mer 5'T G A C C A T C A A T A A G G A A G A A G21 C C C T T C A G C G G C C 3' (ODN binding site underlined) led to an alkali-labile site predominantly (> 90%) at the G21 base, which is at the junction of double-stranded and single-stranded regions of the hybrid. Greater yields were found with Ru-ODN-1 (7) than with Ru ODN-2 (13). In contrast to this specific cleavage with Ru-ODN-1 (7) or Ru-ODN-2 (13), alkali-labile sites were generated at all guanines when the 34mer was photolysed in the presence of the free sensitiser [Ru(phen)3]2+. Since [Ru(phen)3]2+ was shown to react with 2'-deoxyguanosine to form the diastereomers of a spiroiminodihydantoin derivative (the product from 1O2 reaction), 1O2 might also be an oxidizing species in the case of Ru-ODN-1 (7) and Ru-ODN-2 (13). Therefore to determine the range of reaction, a series of 'variant' targets was prepared, in which G21 was replaced with a cytosine and a guanine substituted for a base further towards the 3'-end (e.g. Variant 3; 5'T G A C C A T C A A T A A G G A A G A A C C G23 C T T C A G C G G32 C C3'). While it was noted that efficient reaction took place at distances apparently remote from the photosensitiser (e.g at G32, but not G23 for Variant 3), this effect could be attributed to hairpinning of the single-stranded region of the target. These results are therefore consistent with the photooxidative damage being induced by a reaction close to the photosensitiser rather than by a diffusible species such as 1O2.

Autoradiography↗
PubMed2005

[Establishment of mouse SP2/0 cell line stably expressing bcr-abl fusion gene fragment].

To establish SP2/0 cell line H-2(d) stably expressing bcr-abl fusion gene fragment, the bcr-abl fusion gene was subcloned into retroviral vector pLXSN from pGEMbcr-abl. The recombinant retroviral vector pLXSNbcr-abl was transfected into PT67 packaging cells with the help of lipofectamine. The positive clones were selected out and cultured after G418 selection. Then viral supernatant was collected to determine viral titer, the viral titer was 2 x 10(7) CFU/ml. The SP2/0 cells were infected with the collected viral supernatant. The results showed that after G418 selection, the bcr-abl fusion gene was integrated into the chromosome of SP2/0 cells infected stably, with recombinant retrovirus and expressed in SP2/0 cells confirmed by PCR and RT-PCR respectively. In conclusion, the mouse tumor cell lines expressing the bcr-abl fusion protein were successfully established and would be used as a experimental cell model for anti-CML immunotherapy.

Animals↗
PubMed1991

A complex chromosome rearrangement forms the BCR-ABL fusion gene in leukemic cells with a normal karyotype.

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.

Aged↗
PubMed1998

The presence of typical and atypical BCR-ABL fusion genes in leukocytes of normal individuals: biologic significance and implications for the assessment of minimal residual disease.

The number of genetic lesions necessary to generate leukemia in humans is unknown, but it is possible that certain specific abnormalities, eg, fusion genes, known to be associated with acute and chronic leukemia are produced relatively frequently in human cells but require other events to occur before the leukemia becomes manifest. We investigated this possibility by studying peripheral blood leukocytes from normal individuals and various hematopoietic cell lines for the presence and expression of the p210 and the p190 types of the BCR-ABL gene associated with chronic myeloid leukemia (CML) and acute lymphoblastic leukemia. We used two-step reverse transcriptase-polymerase chain reaction (RT-PCR) assays in which batches of 10(8) cells per sample were tested in 40 replicate reactions. We estimate that this assay is 1.5 logs more sensitive than the two-step RT-PCR assays that we use routinely to assess minimal residual disease. BCR-ABL fusion gene transcripts of various configurations were found in circulating leukocytes from 12 of the 16 healthy adults analyzed. Transcripts with an e1a2 junction (p190 BCR-ABL) were present in 11 and p210-type transcripts with b2a2 and/or b3a2 junctions were detected in 4 individuals. The same RT-PCR assays in non-CML cell lines showed the presence of classical or aberrant p210-type mRNA in 3 of 7 lines and of p190-type transcripts in all 7 lines of hematopoietic origin (HL60, KG1, U937, Kasumi, Jurkat, JVM13, and JVM25), whereas the NIH3T3 murine fibroblast line was reproducibly negative for these fusion genes. These findings confirm and extend previous reports on the detection of leukemia-associated genes in normal leukocytes and suggest that certain fusion genes are generated relatively frequently in hematopoietic cells, but only infrequently do the cells acquire the additional changes necessary to produce leukemia in humans. Although there is only a small probability that such innocent BCR-ABL-carrying leukocytes are detected by conventional RT-PCR assays, they may be the source of some sporadically positive tests in leukemia patients in long-term remission.

3T3 Cells↗
PubMed2005

[Effect of specific siRNA targeting against bcr-abl chimeric gene on chronic myelogenous leukemia cells].

OBJECTIVE: To investigate the effect of specific small interfering RNA (siRNA) targeting against bcr-abl chimeric gene on the biological traits of chronic myelogenous leukemia (CML) cells. METHODS: CML cells of the line K561 transcribing a type of b3: a2 mRNA of bcr-abl chimeric gene were cultured. A 21nt siRNA targeting against the chimeric location of the b3: a2 mRNA of bcr-abl chimeric gene was designed, synthesized, and transfected into the K562 cells as RNA interference group. Another K562 cells were transfected with fluorescein enzyme gene specific siRNA as indifferent controls, or with lipid alone as blank vector controls. Some K562 cells without treatment were used as normal controls. 48 hours after the transfection Western blotting was used to detect the expression of P210bcr-abl fusion protein. 3H-TdR incorporation was used to detect the proliferation activity of K562. Annexin V-fluorescencein isothiocyanate (FITC)/phosphatidylinositol (PI) staining was used to detect the apoptosis of K2562 cells. Flow cytometry was used to observe the cell cycle of K562 cells. Benzidine staining was used to detect the differentiation of K562 cells towards erythrocytic series. Western blotting was used further to detect the expression of apoptosis-related protein Bcl-xL/Bax. RESULTS: (1) In contrast with the control groups, the expression level of bcr-abl chimeric gene was much lower in the RNAi group. (2) (3)H-TdR incorporation test showed time-dependent inhibition of proliferation of K562 cells, reflected in decrease of counts per minute (CPM) value in RNAi group 24 h, 48 h, 72 h, and 96 h after siRNA transfection by 33.06%, 52.25%, 57.64%, and 70.87% respectively (F=17.7, P < 0.01). (3) About 43.2% of K562 cells in the RNAi group were apoptotic 48 h after siRNA transfection (F=13.6, P < 0.01). (4) In contrast with the control groups, the expression of apoptosis-associated protein Bcl-xL was greatly down-regulated; however, the expression of Bax protein showed little change. (5) The percentage of benzidine-positive cells in the RNAi group was 23.5% +/- 3.2%, significantly higher than those in the indifferent control group, blank vector group, and normal control group (2.4% +/- 0.3%, 4.5% +/- 0.5%, and 3.6% +/- 0.2% respectively, all P < 0.01), which meant that part of the K562 cells differentiated towards erythrocytic series. (6) The percentage of G1 phase of K561 cells in the RNA1 group was significantly higher than those of the other groups (F = 6.2, P < 0.05), showing a capture in G1-phase of cell cycle. CONCLUSION: The specific siRNA distinctly inhibits the expression of bcr-abl chimeric gene and influences essential biological traits of K562 cells, which will ultimately result in differentiation or apoptosis of K562 cells.

Dose-Response Relationship, Drug↗
PubMed1998

[Inhibition of apoptosis by bcr-abl fusion gene in K562 cells].

OBJECTIVE: To investigate the effect of bcr-abl fusion gene on CML cell apoptosis. METHODS: Apoptosis of in vitro cultured K562 cells was observed after exposure to synthetic 18-mer antisense oligodeoxynucleotide complementary to the bcr-abl junction (b3a2). RESULTS: Apoptosis of K562 cells was significantly increased associated with inhibition of bcr-abl expression. CONCLUSION: bcr-abl fusion gene formation due to chromosome translocation may be the major mechanism of CML via inhibition of apoptosis.

Apoptosis↗