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At least 217 records · Page 12Linked to original sources
PubMed1994

Molecular requirements for rapid plasmacytoma and pre-B lymphoma induction by Abelson murine leukemia virus in myc-transgenic mice.

Mutants and fusion products of the c-abl gene were used to define some of the molecular requirements for rapid plasmacytoma (PC) and pre-B-lymphoma induction in pristane-treated N-myc transgenic BALB/c mice. A-MuLV induced PCs in 21 of 25 mice with a mean post-pristane latency period of 46 +/- 9 days, compared to 134 +/- 25 days in controls exposed to pristane alone. delta XB, a mutant of type IV c-abl with a deletion of the SH3 domain, was equally effective in inducing PCs in 7 of 7 mice with a latency period of 49 +/- 7 days, indicating that gag sequences are not required for rapid PC induction. The delta XB delta Nar mutant that carried a large C-terminal deletion in addition showed only a negligible activity, if any, suggesting that PC acceleration requires the C-terminal domain in the same way as lymphoid transformation and in contrast to fibroblast transformation. BCR-ABL fusion constructs encoding an 185-kDa protein as in acute leukemia, or a 210-kDa protein as in chronic myelocytic leukemia (CML), did not accelerate pristane-induced PC development in the N-myc transgenic mice, in contrast to their known ability to immortalize lymphoid cells in vitro. Only one of 14 non-transgenic littermates developed a pre-B lymphoma after A-MuLV infection, and none of 10 normal littermates infected with delta XB virus developed a construct-carrying tumor. This result suggests that PC acceleration is due to co-operative interaction of the N-myc transgene and activated abl. Infection of N-myc transgenic bone marrow or spleen cells with A-MuLV in vitro led to the outgrowth of pre-B lymphomas after transplantation to pristane-treated BALB/c recipients. The lymphoma-inducing activity of A-MuLV depends on its high titer, since diluted A-MuLV or the lower-titered delta XB induced only PCs under the same conditions. The v-abl, delta XB and BCR-ABL-carrying viruses generated immortalized lymphoblastoid lines in vitro, regardless of the presence of the N-myc transgene, suggesting that lymphoid transformation is a direct function of appropriate abl sequences in contrast to PC acceleration.

Animals↗
PubMed2000

[Synthesis, Cloning and Expression of a Multiple Epitope Antigen of BCR-ABL Fusion Gene]

Chronic myeloid leukemia (CML) appears an ideal and exciting immunological target. Novel and rational immunotherapy may therefore play an important adjuvant role in the treatment of CML patients. Peptides derived from the BCR-ABL fusion region have been shown to be immunogenic and are able to stimulate the production of BCR-ABL-specific T cell lines and clones. In this study, A 280 bp multiple epitope region of BCR-ABL fusion antigen was designed and synthesized. This region contains three BCR-ABL antigen epitopes which can bind to HLA-A2, HLA-A3 and HLA-DR11 molecules, respectively, and epitopes of cholera toxin B (CTB) and tetanus toxoid (TT) which are able to elicit vigorous T cell responses. The fusion antigen gene has highly been expressed in E. coli and the purified fusion protein reserved satisfied activity and antigenicity. The results of this investigation provided a basis for further research on the developing specific T cell immunotherapy of CML.

Journal Article↗
PubMed1998

A novel BCR-ABL fusion gene (e2/1a) in a patient with Philadelphia-positive chronic myelogenous leukaemia and an aggressive clinical course.

A novel variant BCR-ABL mRNA transcript was detected by reverse transcription polymerase chain reaction (RT-PCR) in a patient with Philadelphia positive (Ph+ve) chronic myelogenous leukaemia (CML) who had an aggressive clinical course. Sequence analysis of the amplified cDNA fragment revealed an in-frame fusion with part of BCR exon e2 joined to part of ABL exon 1a. PCR of genomic DNA from this patient demonstrated that this unusual chimaeric mRNA resulted from breakpoints that fell within each of these exons. This is the first report of breakpoints occurring within both ABL and BCR exons and the first fusion to involve ABL exon 1a.

Base Sequence↗
PubMed2000

Stat5a/b contribute to interleukin 7-induced B-cell precursor expansion, but abl- and bcr/abl-induced transformation are independent of stat5.

The cytokines interleukin 7 (IL-7) and interleukin 4 (IL-4) regulate lymphoid differentiation and function and activate the transcription factor Stat5. Using mice deficient for the 2 highly related transcription factors, Stat5a and Stat5b (Stat5a/b(-/-)), we investigated the role of Stat5 for B-cell differentiation, expansion, and function. Peripheral blood B cells of Stat5-deficient mice are significantly reduced, but no proliferation defects in response to various mitogenic stimuli are found. Also, IgM and IgG1 antibody production and immunoglobulin class switching are not affected. Pre- and pro-B cells of Stat5-deficient animals were found to have reduced responses to IL-7. Pro- and pre-B cells are the target cells of the abl oncogene and numerous studies have suggested that Stat5a/b is essential for transformation by derivatives of the Abelson (abl) gene. To assess the role of Stat5a/b in transformation, we have evaluated the ability of various abl derivatives to transform cells from Stat5a/b-deficient mice in vitro or in vivo. We demonstrate that the absence of Stat5a/b is not essential for the induction of lymphoid or myeloid tumors in vivo or on the ability to transform bone marrow cells in vitro.

Animals↗
PubMed1998

A two-color BCR-ABL probe that greatly reduces the false positive and false negative rates for fluorescence in situ hybridization in chronic myeloid leukemia.

The t(9;22) translocation resulting in the fusion of BCR and ABL genes is pathognomonic in chronic myeloid leukemia (CML) and may be investigated at the molecular level using fluorescence in situ hybridization (FISH). Two-color BCR-ABL probes visualizing one fusion signal (1F FISH) have high false positive rates (FPR) and false negative rates (FNR). The FPR is a result of the random spatial association of probe signals within normal interphase cells so that some cells appear to contain the BCR-ABL fusion gene. The FNR of 1F FISH probes depends on the distance between the BCR and ABL probes hybridized to the BCR-ABL fusion gene (< or =368 kb); the "gap" between the signals causing the cell to be interpreted as normal. To overcome these difficulties, a two-color probe was used, employing four yeast artificial chromosome (YAC) sequences that span the breakpoint regions of the BCR and ABL genes and that visualize the two fusion signals BCR-ABL and ABL-BCR in CML cells (2F FISH). The FNR for the 2F FISH probes was assessed on clonal Ph+ granulocyte-macrophage-colony-forming cell (CFU-GM) derived colonies and was reduced to 0.4% (2/450), compared with an FNR of 13.5% (111/823) with 1F FISH. The FPR in normal mononuclear cells for the 2F FISH was 0. 19 +/- 0.12% (3/1,700), whereas the FPR using 1F FISH was 4.5 +/- 2.3% (63/1,294). The 2F FISH can thus be used to evaluate very small frequencies of BCR-ABL-positive and -negative interphase cells and may be of use in the clinical monitoring of CML.

Adult↗
PubMed1990

A novel variant of the bcr-abl fusion product in Philadelphia chromosome-positive acute lymphoblastic leukemia.

Two patients with Philadelphia chromosome-positive acute lymphoblastic leukemia showed novel variants of the chimeric bcr-abl mRNA. The bcr-abl breakpoint region on cDNA derived from the chimeric mRNA was amplified using the polymerase chain reaction (PCR). Sequence analysis of the breakpoint-containing fragment showed that in both patients exon a2 of the abl gene was deleted, giving rise to an in-frame joining at the mRNA level of 5' bcr sequences to the abl exon a3. These findings were confirmed by Southern blot analysis and cloning of chromosomal DNA. Protein studies showed a bcr-abl protein with heightened tyrosine kinase activity in blast cells of both patients: one of the P190 type, the other of the P210 type. The significance of these findings and the role of this new type of translocation in the disregulation of the abl gene are discussed.

Adult↗
PubMed1995

Possible significance of Ph, zinc and BCR-ABL chimaerism in the pathogenesis of chronic myeloid leukaemia.

Available evidence suggests a double-pathway two-staged genetic alteration in the pathogenesis of Chronic Myeloid Leukaemia (CML). The regular Ph' defect results in BCR-ABL gene chimaerism on the one hand and suppressed synthesis of the protein responsible for Zn absorption on the other. The resulting Zn deficiency leads, through its metalloenzymes, to a low NAP activity and depressed DNA & RNA polymerase activities: the latter necessitates an adaptive mechanism to sustain cell division despite low zinc. This adaptation is in the form of another gene alteration; a point mutation in the BCR-ABL chimaeric gene, now an oncogene, whose onco-proteins are zinc-independent and stimulate cell division more efficiently (though abnormally also) than the polymerases while defying the usual mechanisms regulating DNA synthesis and cell division. Thus it seems possible that assisted transcellular zinc transport could prevent development of CML in Ph'-positive individuals and the enhanced (abnormal) cellular proliferation might be specifically inhibited.

Fusion Proteins, bcr-abl↗
PubMed1987

Establishment and characterization of a cell line, TOM-1, derived from a patient with Philadelphia chromosome-positive acute lymphocytic leukemia.

A new Philadelphia chromosome (Ph1)-positive cell line, designated TOM-1, was derived from bone marrow cells of a patient with Ph1-positive acute lymphocytic leukemia (ALL). The TOM-1 cells were positive for Ia and B1 antigens and terminal deoxynucleotidyl transferase (TdT) but negative for common ALL antigen. Although neither surface Ig nor cytoplasmic Ig was detected, the TOM-1 cells contained rearranged immunoglobulin-H chain genes but retained germ-line kappa chain and germ-line T cell receptor beta-chain genes. These results indicate that the TOM-1 cells reside as the progenitor of pre-B cells. We have investigated the chromosome 22 breakpoint and c-abl gene expression in the TOM-1 cells. We found that the breakpoint on chromosome 22 was within the breakpoint cluster region (bcr) in the TOM-1 cells. We also found the breakpoints within or near bcr in four of six Ph1-positive ALL cases, similar to the findings in Ph1-positive CML cases. Amplification of the c-abl gene was not detected in the TOM-1 cells. The leukemic cells isolated from a patient with CML in myeloid crisis contained a novel 8-kilobase (kb) abl-related messenger RNA (mRNA), but the TOM-1 cells contained c-abl transcripts of only normal sizes, despite the fact that they showed the bcr gene rearrangement.

Antigens, Differentiation, B-Lymphocyte↗
PubMed1996

Detection of the breakpoint cluster region-ABL fusion in chronic myeloid leukemia with variant Philadelphia chromosome translocations by in situ hybridization.

Fluorescence in situ hybridization (FISH) technique has been successfully used to detect the BCR-ABL gene fusion in chronic myeloid leukemia (CML) with the classic form of the Philadelphia chromosome (Ph). We applied FISH to study three CML patients showing variant Ph chromosome (either complex or simple type). The results demonstrate that the use of a yeast artificial chromosome (YAC)-derived probe (D107F9) and a cosmid probe (cos-abl 8), specific for BCR and ABL genes respectively, allows also the detection of the BCR-ABL fusion in CML patients with variant Ph.

Adult↗
PubMed2003

Arsenic trioxide inhibits translation of mRNA of bcr-abl, resulting in attenuation of Bcr-Abl levels and apoptosis of human leukemia cells.

Present studies demonstrate that treatment with arsenic trioxide (AT) lowered ectopically expressed or endogenous levels of Bcr-Abl protein, as well as induced apoptosis of Bcr-Abl-expressing cultured and primary chronic myeloid leukemia cells, including those refractory to imatinib mesylate. Treatment with AT neither affected bcr-abl mRNA transcript levels nor promoted the proteasomal degradation of Bcr-Abl. Importantly, in [(35)S]methionine-labeled leukemia cells, exposure to AT rapidly lowered the levels of the newly synthesized Bcr-Abl, indicating inhibition of bcr-abl mRNA translation. Treatment with AT rapidly inhibited the activity of 3-phosphoinositide-dependent protein kinase-1, as well as of p70 S6 kinase-1. p70 S6 kinase-1 is known to be a positive regulator of the translation of a group of mRNAs that possesses a long and highly structured 5'-untranslated region (UTR) containing a tract of oligopyrimidines (TOP). Because bcr-abl mRNA was discovered to possess a long and highly structured 5'-UTR containing a 12-pyrimidine TOP sequence in its 5'-UTR, we determined the effect of AT in Jurkat cells with ectopic expression of a 5'-UTR-deleted mutant of the bcr-abl gene, i.e., Jurkat/Bcr-Abl (5'UTR-) cells. Treatment with AT neither lowered the levels of the 5'-UTR-deleted mutant of Bcr-Abl nor induced apoptosis of Jurkat/Bcr-Abl (5'UTR-) cells. Taken together, these findings demonstrate a novel mechanism by which AT down-regulates Bcr-Abl levels and induces apoptosis of Bcr-Abl-positive chronic myelogenous leukemia cells.

3-Phosphoinositide-Dependent Protein Kinases↗
PubMed1994

Establishment and characterization of a new Ph1-positive ALL cell line (ALL/MIK) presenting bcr gene rearrangement on bcr-2 and ALL-type bcr/abl transcript: suggestion of in vitro differentiation to monocytoid lineage.

A new Ph1-positive acute lymphoblastic leukemia cell line, designated as ALL/MIK, has been developed from a patient with Ph1-positive acute leukemia. The ALL/MIK cells showed an immunophenotype of common ALL with rearranged JH and Jk genes. The ALL/MIK cells showed no M-bcr rearrangement using Southern blot analysis with either 3' or 5' M-bcr probes, but had the bcr gene rearrangement on bcr-2 within the first intron of the bcr gene. Consistent with this result, the reverse transcriptase-dependent polymerase chain reaction (RT-PCR) assay revealed that the ALL/MIK cells contained the transcript derived fusion of the first exon of bcr gene and the second exon of abl gene. Although the ALL/MIK cells were defined as early pre-B cells by immunophenotypical and genotypical analyses, they were capable of differentiating into monocytoid lineage by when cultured with TPA. Furthermore, another Ph1-positive ALL cell line, (TOM-1), was investigated for its ability to differentiate to monocytoid lineage. TOM-1 was also induced to monocytoid lineage by TPA. Thus, the present study suggested that the leukemic transformation in some Ph1-positive ALL may occur at the level of multipotential hematopoietic cells capable of differentiating towards lymphoid and myelo-monocytoid lineage.

Aged↗
PubMed1993

Antisense inhibition of P210 bcr-abl in chronic myeloid leukemia.

The evidence that the bcr-abl gene product (P210) of the Philadelphia chromosome plays a crucial role in the pathogenesis of chronic myeloid leukemia (CML), and the absence of the bcr-abl fused transcript in non-malignant cells makes this messenger RNA an ideal candidate for antisense strategies in CML. To inhibit the expression of the bcr-abl gene, and to try to eradicate Philadelphia-positive cells, different methods can be used: 1) the introduction into the cells of antisense oligonucleotides, 2) the use of specific ribozymes, or 3) the transduction, using retroviral vectors, of stably integrated sequences coding for antisense RNA. Each of these approaches has potential advantages and drawbacks that are discussed below. Although many data emerge that support the use of anti-bcr-abl antisense molecules in CML, numerous questions remain to be completely answered before the most efficient strategy can be designed, either for in vitro or in vivo purposes.

Animals↗
PubMed1999

Leukemia patient-derived lymphoblastoid cell lines exhibit increased induction of leukemia-associated transcripts following high-dose irradiation.

Improvement in diagnostic cytogenetic techniques has led to the recognition of an increasing number of leukemia-associated chromosomal translocations and inversions. These genetic lesions frequently are associated with the disruption of putative transcription factors and the production of hybrid transcripts that are implicated in leukemogenesis. Epidemiologic evidence suggests that some, but not all, individuals with a history of gamma-irradiation exposure are at increased risk of developing chronic myeloid leukemia (CML). CML is characterized by the Philadelphia chromosome and transcription of the resulting hybrid BCR-ABL gene. Utilizing the leukemia-associated BCR-ABL p210 transcript as a marker, we sought differences in the induction of illegitimate genetic recombination following high-dose gamma-irradiation of karyotypically normal lymphoblastoid cell lines (LCL) derived from individuals with and without a history of myeloid leukemias. Six LCL [4 leukemia patient derived [2 acute myeloid leukemia and 2 CML] and 2 from normal individuals were analyzed with reverse transcriptase polymerase chain reaction for BCR-ABL under stringent conditions following exposure to 0, 50, or 100 Gy of LET gamma-irradiation delivered via a Varian linear accelerator at 4 MV. Transcripts identical to disease-associated b2a2 and b3a2 transcripts were detected both spontaneously (background illegitimate genetic recombination) and following gamma-irradiation. Background BCR-ABL positivity was demonstrable in 4 of the 6 LCL, with no significant difference in detection between leukemic- and nonleukemic-derived LCL. Overall, increasing gamma-irradiation dose resulted in an increased frequency of BCR-ABL transcript detection (0 Gy vs 50 Gy vs 100 Gy,p = 0.0023, Chi-square test). Within the leukemic- but not the nonleukemic-derived LCL there was significantly greater BCR-ABL positivity after gamma-irradiation compared to unirradiated equivalents. Furthermore, the BCR-ABL positivity of both the AML- and CML-derived LCL after gamma-irradiation was significantly greater than that of the nonleukemic-derived LCL after gamma-irradiation. We speculate that this difference in the detection of illegitimate after gamma-irradiation recombination may be due to aberrant DNA double strand break repair mechanisms in individuals predisposed to the development of myeloid leukemias.

Acute Disease↗
PubMed1996

Abnormal peripheral lymphocyte function in c-abl mutant mice.

The proto-oncogene c-abl encodes a tyrosine kinase that is hypothesized to function in proliferation-stimulatory signaling pathways. Previous work on mice homozygous for targeted mutations in the c-abl gene (ablml and abl2 mutant strains) has demonstrated multiple defects, including a susceptibility to infections that results in a high mortality rate after weaning. FACS analysis of the hemopoietic system of c-abl mutants demonstrated variable reductions in B and T lymphocytes in adult bone marrow, thymus, spleen, and peripheral blood. In addition, bone marrow from mutants showed a decreased ability to respond to interleukin-7. We further found that B cells from ablm1 mice had a reduced ability to respond to lipopolysaccharide (decreased to 10% of control response) that was dependent on the culture conditions and the tissue of origin of B cells. Peripheral blood from the mutants also had a reduced response to the T cell mitogen concanavalin A. Immune response in ablm1 mice as determined by the mixed lymphocyte response and the sheep red blood cell plaque-forming assay was grossly normal. These findings suggest that although specific signaling pathways in lymphocytes may involve c-Abl, the immune system can function in the absence of a normal c-abl gene product.

Animals↗
PubMed1999

Identification of a promoter sequence from the BETL1 gene cluster able to confer transfer-cell-specific expression in transgenic maize

The maize (Zea mays L.) betl1 locus, encoding a basal endosperm transfer layer-specific protein, has been mapped and molecularly cloned in its entirety. The locus is shown to consist of three gene copies in the maize inbred line A69Y. To distinguish the three transcription units from the locus name, we have termed them BETL1a, BETL1b, and BETL1c. Two of the copies are expressed, whereas one is inactive and contains retrotransposon-like insertions in both promoter and intron regions. Based on this information, and a restriction site map covering 17 kb around the BETL1 locus, a DNA fragment putatively containing an active promoter sequence was identified. This fragment was tested for its ability to confer transfer-cell-specific expression in transient and stably transformed maize tissues. The transgenic maize plants obtained showed the predicted cell-type specificity of expression restricted to the basal endosperm transfer cells, although there were minor deviations in promoter strength and timing and accumulation of the transgene product from the corresponding BETL-1 endogene expression pattern.

Journal Article↗
PubMed2002

Assessment of minimal residual disease (MRD) in CBFbeta/MYH11-positive acute myeloid leukemias by qualitative and quantitative RT-PCR amplification of fusion transcripts.

The inv(16)(p13q22) chromosomal rearrangement associated with FAB M4Eo acute myeloid leukemia (AML) subtype is characterized by the presence of the CBFbeta/MYH11 fusion transcript that can be used to detect minimal residual disease (MRD). However, qualitative RT-PCR studies of MRD have so far produced conflicting results and seem of limited prognostic value. We have evaluated retrospectively MRD in a large series of CBFbeta/MYH11-positive patients employing both qualitative and quantitative (real-time PCR) approaches. 186 bone marrow samples from 36 patients were examined with a median follow-up of 27.5 months; 15 patients relapsed during follow-up. In qualitative studies, carried out by 'nested' RT-PCR assay, all patients in complete remission (CR) immediately after induction/consolidation therapy were found to be PCR positive. However, follow-up samples at later time points were persistently negative (except one case) in patients remaining in continuous CR (CCR) for more than 12 months. 16 patients were evaluated by quantitative real-time PCR assay: CBFbeta/MYH11 transcript copy number was normalized for expression of the housekeeping gene ABL, expressed as fusion gene copy number per 10(4) copies of ABL. A 2-3 log decline in leukemic transcript copy number was observed after induction/consolidation therapy. After achieving CR, the mean copy number was significantly higher in patients destined to relapse compared to patients remaining in CCR (151 vs 9, P < 0.0001 by Mann-Whitney test). Moreover, in CCR patients, the copy number dropped below the detection threshold after the treatment protocol was completed and remained undetectable in subsequent MRD analysis in accordance with results obtained by qualitative RT-PCR. On the contrary, in the seven patients who relapsed, the copy number in CR never declined below the detection threshold; thus a cut-off value discriminating these two groups of patients could be established. The findings of our study, if confirmed, might confer an important predictive value to quantitative real-time PCR determinations of MRD in patients with inv(16) leukemia.

Adolescent↗
PubMed1992

Oncogene alterations in rat colon tumors induced by N-methyl-N-nitrosourea.

The authors assayed oncogene alterations in rat colon tumors induced by the direct-acting chemical carcinogen, N-methyl-N-nitrosourea (MNU). DNA isolated from 34 adenomas and eight carcinomas, as well as adjacent normal colon, of 11 rats was assayed by Southern blotting for restriction fragment length polymorphisms and gene amplifications and deletions in 13 oncogenes known to be involved in human or other animal tumors. In addition to finding apparent point mutations or other small alterations in the fos and abl genes in individual rat colon tumors, the authors observed what appear to be larger alterations (ie, rearrangements, or intragenic insertions or deletions) in the H-ras and myb loci in several tumors. In contrast, no changes in the K-ras, N-ras, myc, N-myc, neu, raf, fms, met, and hst genes were seen in any of these tumors. The frequency of myb gene alterations was higher in carcinomas than in adenomas, suggesting that these changes occurred relatively late during tumorigenesis and were not direct effects of the carcinogen. In addition, the finding of alterations in two or three oncogenes in several MNU-induced rat colon tumors suggests the possibility of more widespread genomic lesions in this model.

Animals↗