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At least 631 records · Page 35Linked to original sources
PubMed2000

Rapid quantitative detection of BCR-ABL transcripts in chronic myeloid leukemia patients by real-time reverse transcriptase polymerase-chain reaction using fluorescently labeled probes.

BACKGROUND AND OBJECTIVES: The limited value of qualitative reverse transcription polymerase chain-reaction (RT-PCR) for monitoring chronic myeloid leukemia (CML) patients has prompted the development of quantitative assays. We have developed a quantitative real-time PCR (QC-PCR) method in the LightCycler, based on the use of fluorescently labeled probes (HybProbes), to estimate BCR-ABL fusion gene transcripts in samples from CML patients. DESIGN AND METHODS: Fifty-two samples (45 peripheral blood, five bone marrow, and two apheresis product samples) from nine patients with CML were analyzed. Seven patients were studied at diagnosis and during follow-up after hematopoietic stem cell transplantation (HSCT), whereas two were evaluated only after HSCT. The PCR reaction was carried out in capillary tubes in a final volume of 10 microL, using 2 microL cDNA, the Mensik et al. primers, and two HybProbes. The results for BCR-ABL were normalized with reference to ABL. The PCR program is completed in only 45 min. RESULTS: The sensitivity attained allowed the detection of rearrangements at dilutions of between 5-10(-4) and 10(-5) K562 cDNA. The within-assay coefficient of variation was 11% for BCR-ABL, and 9% for ABL. A greater than 2 log reduction in the BCR-ABL/ABL ratio was evident shortly after transplantation in all allografted patients. INTERPRETATION AND CONCLUSIONS: We may conclude that the TaqMan probe technology can be easily adapted to HybProbes with equivalent results. Besides, the results of BCR-ABL quantification in the follow-up of patients clearly confirm that real-time PCR with HybProbes is a reliable and sensitive method for monitoring minimal residual leukemia after HSCT in CML patients.

Adolescent↗
PubMed2002

Relationship of the BCR gene breakpoint and the type of BCR/ABL transcript to clinical course, prognostic indexes and survival in patients with chronic myeloid leukemia.

BACKGROUND: Chronic myeloid leukemia is characterized by the presence of the Philadelphia chromosome. At the molecular level a fusion of part of the ABL and BCR genes is observed. The breakpoint locations in the BCR gene fall between exons b2a2 or b3a2 (5' and 3', respectively). Depending on the BCR gene breakpoint two types of mRNA are created. Differences in the types of transcripts and/or the breakpoint site may have an influence on the clinical course of the disease. This prompted the present author to separate subtypes of chronic myeloid leukemia on the molecular level. MATERIAL/METHODS: 71 patients diagnosed with chronic myeloid leukemia in the chronic phase were enrolled in the study. In 61 patients the type of BCR/ABL transcript was determined, and in 27 patients BCR breakpoints were established. Possible correlations between the clinical course, prognostic indexes, survival and the type of transcript and breakpoint were examined. RESULTS: No correlation between the clinical course, prognostic index, or survival was observed in patients with 5' and 3' breakpoints. The patients with b3a2 transcript experienced longer survival than the patients expressing b2a2 transcript. However, no significant differences were observed in the duration of the chronic phase between the two groups. CONCLUSIONS: The type of BCR gene breakpoint seems to have no prognostic value in patients with chronic myeloid leukemia. The longer survival of patients expressing the b3a2 transcript may be caused by the less aggressive course of the accelerated or blastic phase.

Adolescent↗
PubMed2002

Immunogenicity of a p210(BCR-ABL) fusion domain candidate DNA vaccine targeted to dendritic cells by a recombinant adeno-associated virus vector in vitro.

Chronic myelogenous leukemia (CML) is characterized by a t(9;22) translocation, which results in the expression of chimeric BCR-ABL fusion oncoproteins that are necessary for oncogenesis, unique to the leukemic clones, and represent enticing targets for immunotherapy. As a strategy for the immunotherapy of CML, we constructed a recombinant adeno-associated virus vector encoding the p210(BCR-ABL) b3a2 variant fusion region with flanking sequences (CWRBA) and used it to express the BCR-ABL fusion region within primary human dendritic cells (DCs), the most potent antigen-presenting cells currently known. Peripheral blood mononuclear cells from healthy donors were primed and restimulated in vitro with autologous DCs transduced with purified CWRBA, CWRAP (negative control), or pulsed with a peptide corresponding to the fusion domain (positive control). No specific responses were generated using DCs transduced with CWRAP. In contrast, CWRBA-transduced DCs primed autologous T cells in an antigen-specific, MHC-restricted fashion to levels comparable with the positive control. CWRBA-transduced DCs elicited both cytotoxic CD4+/Th1 and CD8+ responses, although the former were more readily detected in this system. Cytotoxicity against a tumor cell line endogenously expressing the p210(BCR-ABL) b3a2 variant fusion region was also demonstrable. In addition, HLA-DRB5(*)0101+DRA (DR2a) was identified as a new restriction element capable of presenting the b3a2 BCR-ABL fusion region epitope. Thus, the construct developed herein may serve as a candidate vaccine for gene-based antigen-specific immunotherapy of CML and may serve as a paradigm for the use of DCs transduced with recombinant adeno-associated virus vectors encoding multiepitope immunogens for vaccine development.

Amino Acid Sequence↗
PubMed2003

[Influence of irradiation on the dynamic three-dimension distribution of abl and bcr genes in the interphase nuclei of IM-9 cell].

OBJECTIVE: To investigate the material foundation of the fusion of bcr and abl genes, and to explore the pathogenesis of chronic myeloid leukemia. METHODS: By FISH combined with laser confocal scanning microscopy, the three-dimension (3D) distribution of bcr and abl genes in the interphase nuclei of normal and irradiated IM-9 cells was studied in each cell cycle phases. RESULTS: abl and bcr genes distributed non-randomly in the interphase nuclei of IM-9 cells. abl gene preferably located at the outer layer and bcr near the core of the nucleus. The two genes were drawn near each other most in G(0) phase. The relative distance between the homologous genes was greater at proliferation phase than at quiescence phase. After irradiation, the relative distances from the two genes to the core and between the two genes were shortened, with the shortest distance between the two genes in S phase. CONCLUSION: Irradiation could change the 3D-distribution of abl and bcr genes in the interphase nuclei of IM-9 cell and accelerate them to draw near each other.

Cell Nucleus↗
PubMed2003

Synergistic growth inhibitory effects of interferon-alpha and lovastatin on bcr-abl positive leukemic cells.

The chimeric bcr-abl tyrosine kinase is of crucial pathogenic importance in chronic myeloid leukemia (CML). As shown, bcr-abl activates the ras pathway by phosphorylation of adapter proteins such as Grb-2 and Crkl. Functional inhibition of p21ras might partially inhibit the mitogenic signaling by bcr-abl. By depletion of cellular mevalonate pools, p21ras proteins can be rendered non-functional as a result of deficient post-translational protein farnesylation. We investigated the pharmacologic effect of mevalonate depletion by lovastatin in conjunction with interferon-alpha 2b (INF-alpha 2b) in bcr-abl positive K562 cells. At various concentrations, both drugs synergistically reduced cell proliferation of CML line K562 in a liquid culture system as well as clonal growth of colony forming units in a patient with newly diagnosed CML. Lovastatin and IFN-alpha 2b in combination led to cell cycle arrest and resulted in significant reduction of phosphorylation on tyrosine, serine, and threonine protein residues. IFN-alpha 2b alone showed little effect on protein phosphorylation but strongly enhanced lovastatin driven loss of phosphorylation. Subsequently, DNA fragmentation occurred in 50% of cells. In conclusion, exposure to IFN-alpha 2b and lovastatin synergistically inhibited proliferation of bcr-abl positive cells and resulted in loss of protein phosphorylation and subsequent apoptosis in K562 cells. Our in vitro model suggests further investigations are required of the potential value of HMG-CoA reductase inhibitors as adjunct to therapy of CML with interferon.

Antineoplastic Agents↗
PubMed1992

Clonal analysis of bcr-abl rearrangement in T lymphocytes from patients with chronic myelogenous leukemia.

The cytogenetic hallmark of chronic myelogenous leukemia (CML) is the Philadelphia chromosome (Ph1), which reflects a chromosomal translocation t(9;22) and a rearrangement of the ABL and bcr genes. This marker is found in all cells arising from the same malignant precursor cell and can be detected in CML cells of the myeloid, monocytic, erythroid, and B-lymphocyte lineage. It is, however, controversial as to whether T lymphocytes of CML patients carry this gene rearrangement. An answer to this question would clarify whether the translocation in CML occurs in a pluripotent hematopoietic stem cell or in a precursor cell already committed to certain lineages, but not the T-cell lineage. To address this question, we established T-cell clones from peripheral venous blood cells of four patients with CML and screened these clones for bcr-abl fusion transcripts by means of polymerase chain reaction and Southern blot analysis. In four T-cell clones of three of these patients, the bcr-abl transcript could be detected. None of 12 T-cell clones of the fourth patient disclosed detectable bcr-abl amplification product. Both CD4+ as well as CD8+ clones displayed fused bcr-abl sequences. These data imply that in CML some but not all T lymphocytes may originate from the Ph1-positive stem cell.

Blotting, Southern↗
PubMed1992

Antibody recognition of the tumor-specific b3-a2 junction of bcr-abl chimeric proteins in Philadelphia-chromosome-positive leukemias.

The reciprocal translocation between chromosome 9 and chromosome 22, as observed in chronic myeloid leukemia (CML) as well as in acute lymphoblastic leukemia (ALL), results in a 22q- chromosome, the so-called Philadelphia chromosome. The translocation event creates on the Philadelphia chromosome a fusion between two genes: bcr and abl. Depending on the localization of the breakpoint in the bcr gene different chimeric bcr-abl genes are generated, each encoding their own tumor-specific protein: e1-a2P190bcr-abl, b2-a2p210bcr-abl, or b3-a2P210bcr-abl. Especially in ALL, the presence of such a tumor-specific protein is highly associated with a poor prognosis. Detection of these proteins therefore has a strong clinical significance. In this study a polyclonal antiserum, termed BP-2, was raised against a synthetic peptide, corresponding to the tumor-specific 'fusion-point' epitope of the b3-a2P210bcr-abl protein. The specificity of BP-2 for the bcr-abl joining region in b3-a2P210bcr-abl is demonstrated by means of peptide inhibition studies in combination with immunoprecipitation. In addition we show the reactivity of BP-2 with bcr-abl proteins in leukemic cells of a Philadelphia-chromosome-positive ALL patient.

Amino Acid Sequence↗
PubMed2004

[Polymorphism analysis of 5' promotor region of BCR gene].

BACKGROUND & OBJECTIVE: BCR-ABL fusion gene is regarded as the molecular hallmark of chronic myelogenous leukemia (CML), and its expression is controlled by the BCR gene promoter. This study was designed to investigate the polymorphism of the promoter region of BCR gene, and its possible correlation with the disease. METHODS: A 1.13 kb fragment of BCR gene 5' promotor region was amplified and sequenced from 30 CML patients and 19 controls. Transcription factor binding sites and repeat sequences in this region were analyzed using softwares and online tools. RESULTS: Four novel single nucleotide polymorphisms (SNPs) and 3 bases different from the reference sequence were detected in the region studied. Among these 2 novel SNPs and 1 different base were located in or near several bases of binding sites. The gene frequencies of the novel SNPs had no significant difference between CML and control people. CONCLUSION: Sequence polymorphisms were found in the 5' promotor region of BCR gene, most of them being SNPs. No relativity can be validated between the SNPs and the disease. But it appears that some SNPs might have the probability of bringing influence to the transcription and expression of the gene.

Base Sequence↗
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↗
PubMed2005

[Detection and quantification of BCR-ABL transcripts in patients with chronic myeloid leukemia by real-time quantitative reverse transcriptase polymerase chain reaction].

OBJECTIVE: To investigate the effect of real-time quantitative reverse transcriptase polymerase chain reaction (RT-PCR) approach in chronic myeloid leukemia (CML) for detecting the minimal residual disease (MRD) or monitoring the treatment response and predicting the prognosis. METHODS: Fifty-six CML patients, 39 males and 17 females, aged 39 (16 approximately 66), with disease history and frozen RNA specimens were studied, 31 of which were in the incipient chronic phase, 7 in the accelerated phase, and 17 in the rapidly progressing phase. Three or more frozen RNA specimens collected before and after treatment were preserved in 11 of the patients. Breakpoint cluster region-Abelson murine leukemia viral oncogene (BCR-ABL) of the patients in different CML stages was analyzed by RT-PCR approach. RESULTS: The BCR-ABL transcript of those patients remaining in chronic period after treatment decreased to 1/3 that of the baseline level six months after the initiation of treatment and then remained at that level. The BCR-ABL transcript of those in which progressing change occurred increased when such change occurred. After allogeneic transplantation of peripheral blood stem cells the BCR-ABL level decreased significantly. The median DoseN in the 17 progressing patients was 10 492, significantly higher than those of the 31 patients in chronic phase (5920) and in the 7 patients in accelerated phase (4444, both P < 0.05). The minimal residual disease and the treatment response were closely associated with the level and its variation of BCR-ABL transcripts, the transcripts level in blastic crisis was significantly higher than that in chronic phase or accelerated phase. CONCLUSION: Real-time quantitative RT-PCR is reliable and can be used to detect the minimal residual disease, monitor the treatment outcome, and predicting blastic crisis.

Adolescent↗
PubMed1991

BCR-ABL rearrangements in children with Philadelphia chromosome-positive chronic myelogenous leukemia.

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.

Adolescent↗
PubMed1991

Consistent involvement of the bcr gene by 9;22 breakpoints in pediatric acute leukemias.

To investigate the relationship of bcr-abl fusion mRNAs with childhood acute lymphoblastic leukemias (ALL), we examined 27 pediatric Philadelphia chromosome (Ph1)-positive acute leukemias using a reverse polymerase chain reaction (PCR) procedure. In cells from 24 leukemias, single bcr-abl PCR products were detected that corresponded to breakpoints in the minor breakpoint cluster region (mbcr in intron 1 of the bcr gene) associated with production of the P190 fusion protein. Cells from the three remaining leukemias contained breakpoints in the major breakpoint cluster region (Mbcr) as shown by PCR and Southern blot analyses. These three leukemias also contained low levels of the mbcr PCR product that may have resulted from alternative splicing of the bcr-abl precursor RNA. A screen of 35 additional leukemias from patients who failed therapy before day 180 (induction failures or early relapses) found one case with unsuccessful cytogenetics to express Mbcr-abl RNA. All four children with Mbcr breakpoints had white blood cell levels in excess of 250,000 at presentation (compared with 2 of 24 with mbcr breakpoints) and two had hematologic and clinical features suggestive of chronic myelogenous leukemias (CML) in lymphoid blast crisis. Our results indicate that in Ph1-positive pediatric leukemias, all 9;22 breakpoints occur in one of the two known breakpoint cluster regions in the bcr gene on chromosome 22. The reverse PCR reliably detected all patients with cytogenetic t(9;22) and is capable of detecting additional Ph1-positive leukemias that are missed by standard cytogenetics. Furthermore, the Mbcr-type breakpoint, associated with production of p210, can be seen in childhood leukemias presenting either as clinical ALL or as apparent lymphoid blast crisis of CML, suggesting that t(9;22) breakpoint locations do not exclusively determine the biologic and clinical features of pediatric Ph1-positive ALL.

Adolescent↗
PubMed1989

A PvuII polymorphism of the bcr region in patients with hematopoietic disorders and their families.

The BCR gene on chromosome 22 has received increasing attention because of its involvement in the Philadelphia (Ph') translocation. For most restriction enzymes, this locus has been found to be nonpolymorphic. Two alleles have only been found when Taql-digested DNA is hybridized to a 5' bcr-specific probe. We describe another two-allele polymorphism detected by the same probe in PvuII-digested DNA. The polymorphism is characterized by an additional PvuII site in the bcr region: this causes the appearance of an additional band of about 2.3 kb or 2.5 kb besides a 4.8-kb fragment in hybridizations with the 5' bcr or a 3' bcr probe. The incidence of the second allele is very low. It has only been found in some patients with hematopoietic malignancies and in a group of volunteers having a leukemia patient in their families.

Deoxyribonucleases, Type II Site-Specific↗
PubMed1995

Improved specificity of ribozyme-mediated cleavage of bcr-abl mRNA.

Ribozyme-mediated cleavage of bcr-abl mRNA has been shown to be associated with the concomitant cleavage of bcr mRNA. The possible role of this ribozyme as a clinical therapeutic constrained us to improve its target specificity. Consequently, three modified ribozymes (Rz7-9) were created, each carrying a single base mismatch in the sequence immediately 5' of the cleavage site, while a fourth ribozyme (Rz10) was targeted to a nearby site. Each was compared with the parent ribozyme for its ability to cleave synthetic bcr-abl and bcr substrates, and it was shown that alteration of the second base 5' of the cleavage site created a ribozyme with significantly improved specificity for its substrate. Rz10 was shown to exclusively act on bcr-abl, but the efficiency of cleavage was reduced compared to that shown by ribozymes 6, 8, and 9.

Base Sequence↗
PubMed1995

Multi-unit ribozyme-mediated cleavage of bcr-abl mRNA in myeloid leukemias.

Chronic myelogenous leukemia is characterized by the Philadelphia chromosome, which at the molecular level results from the fusion of the bcr gene on chromosome 22 and the abl gene on chromosome 9. The bcr-abl fusion gene encodes a novel tyrosine kinase with transforming activity. In this study, we have synthesized a multi-unti ribozyme that targets bcr-abl mRNA. In vitro ribozyme cleavage reactions show increased cleavage efficiency of this multi-unit ribozyme compared with single or double ribozymes. The multiunit ribozyme was then transfected into murine myeloblasts transformed with the bcr-abl gene (32D cells). Ribozyme transfection was accomplished either by liposomes or using follic acid-polylysine as a carrier. Multi-unit ribozyme transfection reduced the level of bcr-abl mRNA 3 logs when transfected via folate receptor-mediated uptake into transformed 32D cells. These results suggest that a multi-unit ribozyme could be an effective therapeutic agent for the treatment of Philadelphia chromosome-positive chronic myelogenous leukemia.

Animals↗
PubMed1995

Balanced parental contribution to the ABL component of the BCR-ABL gene in chronic myeloid leukemia.

Genomic imprinting has recently been associated with the reciprocal t(9;22) chromosome translocation of chronic myeloid leukaemia (CML). This translocation gives rise to a 22q-, or Philadelphia (Ph), chromosome and a derivative 9q+. Based on heterochromatin polymorphisms, it was reported that the former is of maternal and the latter of paternal origin in every case of CML. This parental bias led to the hypothesis that the genes disrupted by the translocation, BCR and ABL, were themselves imprinted, and that in CML the BCR-ABL gene was formed by BCR sequences of maternal and ABL sequences of paternal origin. We have identified a BstNl restriction fragment length polymorphism in the ABL coding sequence which enabled us to investigate directly the expression and inheritance of the two ABL alleles in heterozygous CML patients. Amplification of the specific BCR-ABL and normal ABL mRNA messages by reverse transcriptase-polymerase chain reaction in these patients showed that the ABL moiety of the BCR-ABL gene has an even chance of being the paternal or the maternal copy. We conclude therefore that there is no parental bias in the origin of the translocated ABL gene and no evidence for genomic imprinting of ABL in CML.

Alleles↗
PubMed1994

[Molecular analysis of bcr-abl mRNA during long-term follow-up of cases of chronic myelogenous leukemia].

Forty cases of Ph1-positive CML patients, who were followed up for a long period, were evaluated for bcr-abl mRNA using RT-PCR. We analyzed the relation of the bcr-abl mRNA subtype to the duration of chronic phase and blast crisis lineage. The mean duration of the chronic phase was 2 years 3 months (2Y3M) in b2-a cases, 1Y11M in b3-a, and 1Y4M in both b2-a and b3-a cases. The myeloid/lymphoid ratio at the blastic phase was 1.0 in b2-a, 0.33 in b3-a, and 2.5 in both mRNA cases. No significant difference was observed in the mean duration of the chronic phase and the frequency of two kinds of blast crisis lineage among different bcr-abl mRNA cases. We also evaluated CML patients in clinical remission after BMT. Bcr-abl mRNA was detectable in 6 of 7 cases (6/7) within 6 months after BMT, all five cases from 6 months to 1 year (1Y), 2/8 at 1Y, 3/7 at 2Y, and 3/7 over 3Y. It suggested the longer time after BMT, the more patients were negative for RT-PCR. In one patient, RT-PCR signal became undetectable at 9Y. This demonstrated that bcr-abl mRNA-positive residual cells could be eradicated long after BMT.

Adolescent↗
PubMed1994

BCR-ABL maintains resistance of chronic myelogenous leukemia cells to apoptotic cell death.

Apoptosis is the major form of cell death associated with the action of chemotherapeutic agents on tumor cells, and therefore the expression of genes that interfere with apoptosis can have important consequences for the efficacy of therapeutic approaches. Here we show that K562, a chronic myelogenous leukemia (CML) cell line expressing the BCR-ABL fusion protein, are resistant to the induction of apoptosis by a number of agents and conditions. Antisense oligodeoxynucleotides corresponding to the translation start of bcr downregulate bcr-abl protein in these cells and render them susceptible to induction of apoptosis by chemotherapeutic agents or serum deprivation. Expression of a temperature sensitive v-Abl protein reverses the effects of the antisense oligonucleotides, such that the cells remain resistant to apoptosis at the permissive temperature. These data indicate that bcr-abl acts as an anti-apoptosis gene in CML cells and suggests that the effect is dependent on the abl kinase activity in this chimeric protein. Inhibition of bcr-abl to render CML cells susceptible to apoptosis can be combined with therapeutic drugs and/or treatment capable of inducing apoptosis to provide an effective strategy for elimination of these cells.

Apoptosis↗