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PubMed1999

The nuclear topography of ABL, BCR, PML, and RARalpha genes: evidence for gene proximity in specific phases of the cell cycle and stages of hematopoietic differentiation.

The mechanisms whereby chromosomal translocations are consistently associated with specific tumor types are largely unknown. A generally accepted hypothesis is that the physical proximity of the involved chromosomal regions may be one important factor in the genesis of these phenomena. Accordingly, a likely possibility is that such a proximity may occur in a cell-lineage and cell-differentiation stage-specific manner. In this work, we have addressed this issue using as models the ABL and BCR genes of t(9;22) and the PML and RARalpha genes of t(15;17). By using in situ hybridization and confocal microscopy, we have measured the distances between these two pairs of genes in three-dimensionally preserved hematopoietic cells belonging to different cell lineages, at various stages of differentiation, and at various stages of the cell cycle, with the following results. (1) Intergenic distances vary periodically during the cell cycle and a significant association of ABL with BCR and of PML with RARalpha is seen at the transition between S and G2, which persists during G2 and prophase (such a behavior is not observed for distances between ABL or PML and the beta-globin genes, used as a control). (2) The proportion of cells in which PML and RARalpha or ABL and BCR are closely associated is higher in hematopoietic precursors than in B-lymphoid cells (whereas the distances between ABL or PML and the beta-globin genes are not affected by cell type). (3) When intergenic distances in unstimulated bone marrow CD34(+) cells were compared with those in CD34(+) cells treated with interleukin-3 (IL-3), a trend towards a higher proximity of the ABL and BCR genes in the former and of the PML and RARalpha genes in the latter is observed. (4) Analysis of B-lymphoid cells during mitosis shows that intergenic distances at metaphase are strongly influenced by physical constraints imposed by the chromosomal location of the gene, by the size of the respective chromosome, and by the geometry of the metaphase plate. These findings suggest that intrinsic spatial dynamics, established early in hematopoiesis and perpetuated differentially in distinct cell lineages, may facilitate the collision of individual genes and thus reciprocal recombination between them at subsequent stages of hematopoietic differentiation.

Cell Cycle↗
PubMed2003

T cell receptor-independent basal signaling via Erk and Abl kinases suppresses RAG gene expression.

Signal transduction pathways guided by cellular receptors commonly exhibit low-level constitutive signaling in a continuous, ligand-independent manner. The dynamic equilibrium of positive and negative regulators establishes such a tonic signal. Ligand-independent signaling by the precursors of mature antigen receptors regulates development of B and T lymphocytes. Here we describe a basal signal that controls gene expression profiles in the Jurkat T cell line and mouse thymocytes. Using DNA microarrays and Northern blots to analyze unstimulated cells, we demonstrate that expression of a cluster of genes, including RAG-1 and RAG-2, is repressed by constitutive signals requiring the adapter molecules LAT and SLP-76. This TCR-like pathway results in constitutive low-level activity of Erk and Abl kinases. Inhibition of Abl by the drug STI-571 or inhibition of signaling events upstream of Erk increases RAG-1 expression. Our data suggest that physiologic gene expression programs depend upon tonic activity of signaling pathways independent of receptor ligation.

Adaptor Proteins, Signal Transducing↗
PubMed1989

Suppression of the thermosensitive DNA ligase mutations in Escherichia coli K12 through modulation of gene expression induced by phage Mu.

We have previously shown that Mu can sustain the growth at non-permissive temperature of an Escherichia coli strain harbouring a thermosensitive mutation in the DNA ligase structural gene. This "complementation" reaches a maximal level with the Mu lig3 mutant which restores the viability of a ligts7 strain to the level of the wild type (Ghelardini et al. 1980; Paolozzi et al. 1980). In this study we analysed the characteristics of this phenotypic suppression in order to clarify its molecular mechanism. We found that an E. coli ligts7 strain lysogenic for the Mu lig3 mutant shows: (i) an increment in the host DNA ligase activity; (ii) an increase in the specific mRNA of the host lig gene; (iii) an increase (towards the relaxed state) in the average linking number of a resident plasmid; and (iv) a reduction in DNA gyrase activity. These results are compatible with the hypothesis that the Mu lig gene product by interfering with the host enzymatic apparatus controlling DNA topology leads to a reduction in chromosomal supercoiling. The relaxation of the chromosome could affect the transcription of the DNA ligase gene, amongst others. Thus, through this mechanism, the Mu lig gene product is able to modulate gene expression and hence suppress the effects of the E. coli ligts7 mutation. On the basis of the identification of this mechanism of action, we propose to change the name of the Mu lig gene (thought originally to be the structural gene for a bacteriophage ligase) to gem (gene expression modulation).

Bacteriophage mu↗
PubMed1992

Chorion gene cis-regulatory DNA restricts tissue specificity of reporter gene expression in transformed Drosophila.

P element mediated germ-line transformation was used to study the developmental specificity of Drosophila chorion gene regulatory sequences directing expression of the bacterial reporter genes for chloramphenicol acetyltransferase (CAT) and beta-galactosidase (lacZ). DNA fragments containing 5' flanking plus the entire 5' untranslated and the beginning of the coding region of either the s36 or the s15 chorion gene are able to confer on the reporter genes normal tissue as well as temporal specificity of expression, exclusively in the ovary of transformed female flies. However, if 5' untranslated and coding regions are omitted, normal ovarian expression is maintained but tissue specificity is relaxed: expression of the reporter gene is detected both in the ovary and in specific non-ovarian tissues of transformed females and males. The evidence suggests that the missing 5' untranslated and coding sequences may include negative elements that normally suppress expression in non-ovarian tissues, and that these putative elements are distinct from those that prevent premature expression in the ovarian follicles. The exact location of ectopic lacZ expression within the internal male genitalia depends on the constellation of 5' flanking chorion regulatory sequences included in the P element constructs. Ectopic expression of the CAT gene in the male genitalia under s15 promoter control can be abolished by mutating the hexamer TCACGT, a sequence previously shown to be essential for the normal expression of this chorion gene in the ovary.

Animals↗
PubMed2005

BCR/ABL modifies the kinetics and fidelity of DNA double-strand breaks repair in hematopoietic cells.

The oncogenic BCR/ABL tyrosine kinase facilitates the repair of DNA double-strand breaks (DSBs). We find that after gamma-irradiation BCR/ABL-positive leukemia cells accumulate more DSBs in comparison to normal cells. These lesions are efficiently repaired in a time-dependent fashion by BCR/ABL-stimulated non-homologous end-joining (NHEJ) followed by homologous recombination repair (HRR) mechanisms. However, mutations and large deletions were detected in HRR and NHEJ products, respectively, in BCR/ABL-positive leukemia cells. We propose that unfaithful repair of DSBs may contribute to genomic instability in the Philadelphia chromosome-positive leukemias.

Animals↗
PubMed1986

Complementation of Agrobacterium tumefaciens tumor-inducing aux mutants by genes from the T(R)-region of the Ri plasmid of Agrobacterium rhizogenes.

In this paper we provide information indicating that the agropine-type root-inducing (Ri) plasmid pRi1855 of Agrobacterium rhizogenes contains functional genes for auxin production (aux) in the right transferred DNA (T-DNA) region (T(R)-region). These genes were cloned and introduced into the T-region of the tumor-inducing (Ti) plasmids of mutants of Agrobacterium tumefaciens carrying an aux mutation. Depending on the Ri aux gene present, the oncogenicity of the Ti aux-1 and/or aux-2 mutations was restored, showing that the Ri aux genes are able to complement the Ti aux genes. Agrobacterium strains with an agropine-type Ri plasmid not only cause hairy root on certain plant species, but they also induce tumors on other plant species. In this paper it is shown that a mutation in either of the aux genes in the Ri plasmid leads to a total loss of tumorigenicity and a strongly diminished rhizogenicity of the host bacterium, revealing that the aux genes are important for tumor and root induction. Agrobacterium strains containing the T(R)-region but not the T(L) (left)-region of the Ri plasmid are still tumorigenic on certain plant species but are no longer capable of hairy-root induction.

Journal Article↗
PubMed1988

Three spontaneous H-2Db mutants are generated by genetic micro-recombination (gene conversion) events. Impact on the H-2-restricted immune responsiveness.

Sequence analysis of the mutant Dbm13, Dbm14, and Dbm24 genes indicate that they differ from the parental Db gene by 4, 1, and 8 nucleotides, respectively. The mutant sequences substituted into Dbm13 and Dbm24 are identical to those found in the Kb gene, at the homologous positions. Thus, similar to the Kb gene, the Db gene is able to undergo micro-recombination (gene conversion) events with other class I genes. Such data suggest that micro-recombination events could be an important mechanism for the diversification of all H-2 genes. The Db mutant products share a common theme: the alterations in all occur at amino acid residues whose side chains in the homologous class I HLA-A2 molecule project into the postulated peptide antigen-binding cleft, and hence, would be expected to alter the binding of foreign or self peptides. Due to such changes, the bm14 mouse has become a nonresponder in the CTL response to Moloney murine leukemia virus (M-MuLV), as the alteration of one amino acid residue at position 70 (a Gln to His) is sufficient to entirely abrogate the cell-mediated response to the virus. On the other hand, the bm13 mouse has shifted the major part of its M-MuLV restriction to Kb, a profound alteration in CTL responsiveness due to the alteration of three amino acids (Leu to Gln at 114, Phe to Tyr at 116, and Glu to Asp at 119) in a peptide stretch of beta-pleated sheet structure lining the bottom of the antigen-binding cleft. Thus, study of these mutants reveals that, in one step, micro-recombination at the genetic level has resulted at the protein level in profound changes in the immune response to viral infection. Such a mechanism operating at the population level can be a driving force during evolution for modulating the character of CTL immunity.

Amino Acid Sequence↗
PubMed1984

Characterization of enhancer elements in the long terminal repeat of Moloney murine sarcoma virus.

A series of recombinant molecules were constructed which direct the expression of the easily assayed gene chloramphenicol acetyltransferase. We have used these recombinants to show that the 73/72-base-pair tandem repeat unit from the Moloney murine sarcoma virus long terminal repeat shares a number of properties with the prototypic enhancer element, the simian virus 40 72-base-pair repeat. Specifically, the Moloney murine sarcoma virus sequence significantly enhances the level of gene expression at both 5' and 3' locations and in either orientation relative to the test gene. It is able to enhance gene activity both from its own promoter and from a heterologous (simian virus 40) promoter. The 73/72-base-pair subunits of the Moloney murine sarcoma virus enhancer differ in sequence by four nucleotides and also in the strength of their enhancer function. The promoter distal A repeat is at least three times as active as the promoter proximal B repeat in enhancing chloramphenicol acetyltransferase expression. Results of these studies also show that the enhancer sequence alone is unable to induce gene activity but requires other promoter elements, including a proximal GC-rich sequence and the Goldberg-Hogness box.

DNA, Viral↗
PubMed2006

Activation of Abl tyrosine kinases promotes invasion of aggressive breast cancer cells.

The Abl family of nonreceptor tyrosine kinases consists of two related proteins, c-Abl and Abl-related gene (Arg). Activated forms of the Abl kinases (BCR-Abl, Tel-Abl, and Tel-Arg) induce the development of human leukemia; it is not known, however, whether Abl kinases are activated in solid tumors or whether they contribute to tumor development or progression. Previously, we showed that Abl kinases are activated downstream of growth factor receptors, Src family kinases, and phospholipase Cgamma1 (PLCgamma1) in fibroblasts and influence growth factor-mediated proliferation, membrane ruffling, and migration. Growth factor receptors, Src kinases, and PLCgamma1 are deregulated in many solid tumors and drive tumor invasion and metastasis. In this study, we found that Abl kinases are constitutively activated, in highly invasive breast cancer cell lines, downstream of deregulated ErbB receptors and Src kinases. Furthermore, activation of Abl kinases promotes breast cancer cell invasion, as treatment of cells with the Abl kinase inhibitor, STI571, or silencing c-Abl and Arg expression with RNA interference dramatically inhibits Matrigel invasion. This is the first evidence that (a) Abl kinases are deregulated and activated in a nonhematopoietic cancer, (b) activation of Abl kinases in breast cancer cells occurs via a novel mechanism, and (c) constitutive activation of Abl kinases promotes invasion of breast cancer cells. These data suggest that pharmacologic inhibitors targeted against Abl kinases could potentially be useful in preventing breast cancer progression in tumors harboring activated Abl kinases.

Breast Neoplasms↗
PubMed1990

ras gene mutations in human prostate cancer.

Point mutations at codons 12, 13, or 61 of the Ha-, Ki-, and N-ras genes are able to convert these normal cellular genes into activated oncogenes. Previous studies have shown that ras gene mutations occur in a variety of human solid tumors and may be important in the pathogenesis of some of these tumors. In order to test the hypothesis that ras gene mutations may be associated with prostate cancer, we have used an oligodeoxynucleotide hybridization assay to detect wild-type and mutant alleles in genomic DNA from prostate tumors and prostate tumor cell lines amplified using the polymerase chain reaction. Twenty-four primary prostate tumors (23 acinar tumors and one ductal tumor) and five prostate tumor cell lines were examined for mutations at codons 12, 13, and 61 of the Ki-ras, Ha-ras, and N-ras genes. Two mutations were detected: an A----G transition causing a glutamine to arginine amino acid substitution at codon 61 of the Ha-ras gene in a primary prostatic duct adenocarcinoma and a G----T transversion causing a glycine to valine amino acid substitution at codon 12 of the Ha-ras gene in a prostate tumor cell line (TSU-PR1) derived from a lymph node metastasis. While the overall frequency of ras gene mutations in prostate tumors is low, when these mutations do occur they may have a role in the progression of disease or the development of the unusual ductal variant of prostatic adenocarcinoma.

Adenocarcinoma↗
PubMed1996

Recognition of BCR-ABL positive leukemic blasts by human CD4+ T cells elicited by primary in vitro immunization with a BCR-ABL breakpoint peptide.

In chronic myeloid leukemia (CML) the classical 9;22 translocation results in a BCR-ABL fusion gene, which encodes chimeric BCR-ABL fusion 210 kD oncoproteins (p210BCR-ABL). The two main p210BCR-ABL fusion variants in CML, b2a2 and b3a2 are examples of well characterized antigens expressed by malignant cells. The possibility of an immunotherapeutic approach involving the fusion part of p210BCR-ABL in CML has previously been illustrated by observed peptide binding to major histocompatibility complex (MHC) class I alleles and by demonstrating the immunogenicity of p210BCR-ABL breakpoint peptides. In this report we show that in vitro immunization of human T cells with a 17 amino acid (aa) peptide representing the p210BCR-ABL fusion region resulted in peptide specific CD4+ T-cell lines designated P4, P6, and P7. HLA DR4 (DRB1*0401) restricted T-cell line P4 and several subsequently derived clones recognized HLA-DRB1*0401 and p210b3a2-mRNA expressing blasts from an allogeneic patient with CML in blast crisis. Recognition appeared DR expression-dependent. No responses were observed with DR4 positive p210BCR-ABL negative cells or with p210b3a2 leukemic cells with absent or insufficient expression of DR4. These observations indicate that oncoprotein p210b3a2 can be degraded and processed for presentation by MHC class II molecules at the surface of leukemic cells. The BCR-ABL fusion region is in all likelihood presented as peptides by HLA DR and thus capable to act as a distinctive tumor antigen to peptide specific CD4+ T cells.

Amino Acid Sequence↗
PubMed1990

Isolation of DNA insertion elements from Rhizobium meliloti which are able to promote transcription of adjacent genes.

In order to select insertion sequences able to promote transcription of flanking genes (ISp elements), three mobilizable RSF1010 derived vectors were constructed. Using promoterless antibiotic resistance genes, ISp elements ranging from 0.75 to 2.9 kb were isolated from Escherichia coli and Rhizobium meliloti. Restriction and hybridization experiments revealed that identical ISp elements could be isolated from different R. meliloti strains and that one of these is similar to an insertion sequence found previously in R. meliloti 2011.

Cloning, Molecular↗
PubMed2002

Transient response to imatinib mesylate (STI571) in a patient with the ETV6-ABL t(9;12) translocation.

We report the transient response of a patient with the ETV6-ABL fusion gene to imatinib mesylate (STI571). A 38-year-old man was referred with an erroneous diagnosis of Philadelphia-positive chronic myeloid leukemia in blastic transformation for treatment with the ABL tyrosine kinase inhibitor, STI571. Further investigation indicated that the patient in fact had acute myeloid leukemia; no evidence of the Philadelphia translocation or BCR-ABL was found using fluorescence in situ hybridization (FISH) or reverse transcription-polymerase chain reaction. Detailed FISH analysis identified a cryptic t(9;12) translocation, and molecular studies confirmed the presence of the ETV6-ABL fusion transcript. Because the patient was gravely ill at presentation, treatment was commenced immediately with STI571 monotherapy, resulting in considerable initial improvement. However within 10 days the patient's condition again deteriorated, and he required conventional chemotherapy. This case has implications for the design of future studies using STI571 in leukemias involving ABL-encoded fusion proteins other than BCR-ABL.

Acute Disease↗
PubMed1994

Detection of the Philadelphia chromosome in paraffin-embedded tissue by fluorescence in situ hybridization.

The bcr-abl fusion gene situated on the Philadelphia chromosome is a tumor-specific marker for chronic myelogenous leukemia. We evaluated the usefulness of two color fluorescence in situ hybridization with bcr and abl probes as a means of detecting the Philadelphia chromosome in formalin-fixed, paraffin-embedded sections of spleen and lymph node specimens from eight patients with myeloproliferative diseases showing clinical and morphological features of chronic myelogenous leukemia in accelerated phase. Our analysis showed co-localized hybridization signals corresponding to the bcr-abl fusion product in tissue sections from six patients previously found to have the Philadelphia chromosome by conventional cytogenetics and polymerase chain reaction. The two remaining specimens lacked bcr-abl fusion signals and were obtained from patients who were negative for the Philadelphia chromosome by cytogenetic and polymerase chain reaction analysis. We conclude that fluorescence in situ hybridization is a sensitive method for the detection of the bcr-abl fusion gene in histological specimens from patients with chronic myelogenous leukemia. The technique may become a useful tool in the evaluation of tissue specimens from patients with chronic myelogenous leukemia and related Philadelphia chromosome-positive hematologic malignancies.

Fusion Proteins, bcr-abl↗
PubMed2005

[Comparison of therapeutic effects of low-dose versus high-dose interferon alpha-2b treatment on chronic myelocytic leukemia: a prospective randomized study].

OBJECTIVE: To compare the therapeutic effects of low-dose and high-dose interferon alpha-2b (IFN) treatment on chronic myelocytic leukemia (CML). METHODS: A real-time quantitative reverse transcriptase PCR (RQ-PCR) method was established to detect the fusion gene bcr-abl expression, thereby studying the reduction of leukemic cells. Thirty newly diagnosed CML patients, 21 males and 9 females, aged 14 - 69, were treated with hydroxyurea to keep the white blood cell count less than 20 x 10(9)/L, and then randomized into 2 groups: high-dose IFN group receiving IFN alpha-2b 5MIU 6 times per week for 3 - 6 months and low-dose IFN group receiving IFN alpha-2b 3MIU every other day for 3 - 6 months. Bone marrow was collected every month to Real-time PCR was used to detect the expression of bcr-abl mRNA. Mononuclear cells were isolated and RNA was extracted to detect the expression of fusion gene bcr-abl and a control gene GAPDH. The results were reported as the number of bcr-abl copies/GAPDH copy. RESULTS: The established real-time quantitative PCR method could detect the bcr-abl molecules as low as 50 copies. The intra-assay coefficient of variation (CV) was less than 5% and the inter-assay CV was 5.13%. The median bcr-abl fusion gene expression level of 30 CML patients before IFN therapy was 0.098 (range: 0.010 - 5.799). The bcr-abl expression level decreased by 19.37% and 24.86% in the low-dose and high-dose IFN groups respectively after 3 months' therapy. No significant difference was observed between the two groups (P = 0.398). Relatively more side effects were observed in the high-dose IFN group than in low-dose group. CONCLUSION: RQ-PCR is a reliable method to monitor CML therapy by analyzing fusion gene bcr-abl expression. There is a difference in bcr-abl fusion gene expression levels among the newly diagnosed patients, and low-dose IFN is as effective as high-dose IFN in reducing bcr-abl expression but with less side effects.

Adolescent↗
PubMed1989

Differential effect of the autoimmune Yaa and lpr genes on the acceleration of lupus-like syndrome in MRL/MpJ mice.

The Yaa gene (Y chromosome-linked autoimmune acceleration), linked to the BXSB/MpJ Y chromosome, and the autosomal recessive lpr (lymphoproliferation) gene have been shown to accelerate the progression of the lupus-like autoimmune syndrome in the BXSB and MRL strains, respectively. To compare more directly the role of the Yaa and lpr genes in the development of the autoimmune syndrome, the Y chromosome of BXSB mice was transferred to MRL mice by backcross procedures, and the effect of the Yaa gene on the autoantibody formation and the development of lupus-like nephritis in MRL mice was investigated in comparison with those bearing the lpr mutation. The Yaa gene as well as the lpr gene were able to shorten the life span of MRL mice as a result of the accelerated development of lethal lupus-like nephritis. However, the acceleration promoted by the Yaa gene (50% mortality rate: 12 months) was less severe than that induced by the lpr gene (50% mortality rate: 7 months). This may be related to the finding that the lpr gene enhanced the production of a large spectrum of autoantibodies, including anti-DNA, rheumatoid factors and anti-gp70, and of cryoglobulins, whereas only anti-gp70 production among the autoantibodies studies was markedly enhanced by the Yaa gene. The selective autoimmune accelerating effect of the Yaa gene was similarly observed in (NZW X MRL)F1 hybrid mice. Our results suggest that the Yaa gene, unlike the lpr gene, exhibits selective autoimmune accelerating activity, but as a result of increased formation of certain nephritogenic autoantibodies such as anti-gp70 antibodies, the Yaa gene is able to accelerate the progression of lupus-like nephritis in lupus-prone mice.

Animals↗
PubMed1995

Interferon response in chronic myeloid leukaemia correlates with ABL/BCR expression: a preliminary study.

alpha-Interferon (IFN) has been used to induce cytogenetic remission in chronic myeloid leukaemia (CML), but there are few indicators to predict IFN response. The role of the chimaeric BCR/ABL gene in the malignant process is undisputed. There are, however, conflicting views as to whether the breakpoint site within the BCR gene, and the type of mRNA produced determine disease prognosis and progression. The function and clinical significance of the newly discovered ABL/BCR mRNA has not been investigated for a correlation with CML prognosis or response to therapy. We have used a two-step reverse transcriptase polymerase chain reaction (RT-PCR) to detect the transcripts of the chimaeric genes BCR/ABL, ABL/BCR, as well as the normal ABL and BCR genes in 24 CML patients treated with IFN. Because of the variable expression of the four transcripts at presentation, a correlation between gene expression, prognosis and clinical progression was examined. No correlation between prognosis and gene expression was seen. Also, no correlation was found between expression of BCR, ABL or BCR/ABL mRNA and response to treatment with IFN. However, 7/10 ABL/BCR mRNA positive patients achieved a major cytogenetic response to IFN; but of the 13 ABL/BCR mRNA negative patients, only two achieved a major cytogenetic response (P = 0.013). Further studies are required to confirm these findings.

Adolescent↗