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PubMed1994

Unmodified phosphodiester antisense oligodeoxynucleotides to the BCR-ABL junction do not suppress Philadelphia-positive clonogenic cells.

The BCR-ABL fusion gene is directly involved in the pathogenesis of chronic myeloid leukemia (CML). Specific inhibition of the BCR-ABL gene expression with antisense oligodeoxynucleotides has been shown to have profound effects on cell growth in vitro. We examined antisense phosphodiester oligonucleotides (16-mers at a concentration of 60 micrograms/ml) spanning the two possible junction sites K28 (b3a2) and L6 (b2a2) in a clonogenic assay. Single colonies from 9 patients with CML and from patients with normal bone marrow were screened for BCR-ABL expression with a new 'single-tube nested PCR' method. There was a marked reduction in colony number in the CML group and a lesser growth inhibition in the control group. The number and percentage of BCR-ABL-positive colonies, however, was not reduced in the CML group. This indicates a nonspecific growth inhibition only.

Base Sequence↗
PubMed2005

[Ten years of molecular monitoring of chronic myeloid leukemia by quantitative RT-PCR].

Chronic myeloid leukemia (CML) is characterized by the presence of BCR-ABL fusion gene resulting from the reciprocal chromosome translocation t(9;22)(q34;q 11), karyotypically detected as Ph chromosome. BCR-ABL gene was proved to play the principal role in CML pathogenesis. It is a hallmark of CML used in diagnostics and monitoring of the response to the therapy. The most sensitive method of detecting BCR-ABL aberration is RT-PCR which is able to find a single in leukemic cell between 10(6) normal leukocytes. Monitoring of BCR-ABL transcript level by quantitative RT-PCR is of the high prognostic value. High or increasing BCR-ABL transcript number signalizes bad response to treatment and a bad prognosis. On the contrary RT-PCR negativity, low level, or decreasing BCR-ABL transcript number denotes good response to treatment and good prognosis. Q-RT-PCR can detect changes in disease status several weeks or even months earlier than other methods. In 1994 the Q-RT-PCR was introduced at the Institute of Hematology and Blood Transfusion in Prague and was used for early detection of relapse after transplantation. At present it is used in all patients with CML for monitoring of response to the treatment. We have confirmed that this precise, sensitive and non-invasive method is of the principal importance for monitoring of disease status in CML patients.

Fusion Proteins, bcr-abl↗
PubMed1993

Synthesis and conformational studies on peptides corresponding to a putative autophosphorylation site of abl TPK.

The transforming gene of Abelson murine leukaemia virus (v-abl) codes for a membrane-associated tyrosine-specific protein kinase (abl TPK). Analysis of the v-abl gene has shown that both the fibroblast-transforming and tyrosine-protein kinase activities reside within a minimal region encoding a protein of 43 kDa (p43v-abl), which represents the most active, isolated form of this enzyme. Since the cellular substrates for p43v-abl are yet to be identified, we synthesized by classical solution methods the octapeptide H-Gly-Asp-Thr-Tyr-Thr-Ala-His-Ala-OH, corresponding to the structural sequence of the main putative autophosphorylation site (Tyr 515) of the abl TPK, as well as some of its analogs modified in positions -2, -1, +1 and +3. The synthetic peptides were tested as substrates for the p43v-abl. The kinetic data obtained indicate that the rates of their phosphorylation vary considerably depending on the sequence of the peptide, as expected. As a rule, no significant increment of the efficiency results from each substitution in the parent sequence. While the replacement of the two charged residues, namely Asp-2 and His-7, with neutral Ala is well tolerated, the substitution with amino acids bearing opposite charges is detrimental. The correlation between secondary structure of our synthetic octapeptides and their substrate recognition by p43v-abl was studied using CD and fluorescence spectroscopy in 5 mM Tris, in 98% TFE/Tris and in 30 mM SDS solutions. The comparison of the spectroscopic data with the kinetic parameters does not confirm a close relationship between the conformational properties of these peptides and their enzymatic role.

Amino Acid Sequence↗
PubMed1998

Detecting residual bcr-abl transcripts in chronic myeloid leukaemia patients using coupled reverse transcriptase-polymerase chain reaction with rTth DNA polymerase.

The bcr-abl fusion gene is the hallmark of chronic myeloid leukaemia (CML) and presumably the cause of its development. Accordingly, long-term disappearance of the bcr-abl gene after intensive therapy suggests that a patient is probably cured of CML. The diagnostic protocol based on coupling of two enzymatic reactions, reverse transcription (RT) and nested polymerase chain reaction (nPCR), for the detection of bcr-abl transcripts in peripheral blood provides a powerful tool for minimal residual CML detection. We have developed a new detection protocol using rTth DNA polymerase as the only enzyme catalysing both reactions for simplifying CML diagnosis. We demonstrate its efficacy investigating residual leukaemic cells in the peripheral blood of 10 patients. This assay offers several advantages over the use of conventional RT-PCR, being more sensitive, faster, less prone to false positives since no opening of the tube is required between the two reactions and requires no special oils or waxes. Our simple assay for bcr-abl chimeric transcripts detection is a practical addition to the diagnostic evaluation of the patient with chronic myeloid leukaemia.

DNA-Directed DNA Polymerase↗
PubMed1983

The human v-abl cellular homologue.

A contiguous region of cellular DNA sequence, 64 kb in length and representing overlapping cellular inserts from three independent cosmid clones, has been isolated from a representative library of human lung carcinoma DNA partially digested with MboI. Within this region of the cellular genome, v-abl homologous sequences are dispersed over a total region of around 32 kb. These sequences represent the entire v-abl human cellular homologue, are colinear with the viral v-abl transforming gene, and contain a minimum of seven intervening sequences. At least eight regions of highly repetitive DNA sequences have been shown to map in close proximity to c-abl coding sequences. In addition to the major c-abl human locus, three regions of human DNA sequence, corresponding to only portions of the v-abl gene, have been identified. Two of these have been molecularly cloned and shown to be distinct from the primary human c-abl locus. Upon transfection to rat embryo fibroblasts in culture, none of the cosmid DNAs containing v-abl homologous sequences exhibited transforming activity. These findings identify and map a single genetic locus of human DNA, c-abl, representing the complete v-abl homologue, and demonstrate the existence of additional human DNA sequences corresponding to more limited, subgenomic regions of v-abl.

Abelson murine leukemia virus↗
PubMed2006

KLF4 suppresses transformation of pre-B cells by ABL oncogenes.

Genes that are strongly repressed after B-cell activation are candidates for being inactivated, mutated, or repressed in B-cell malignancies. Krüppel-like factor 4 (Klf4), a gene down-regulated in activated murine B cells, is expressed at low levels in several types of human B-cell lineage lymphomas and leukemias. The human KLF4 gene has been identified as a tumor suppressor gene in colon and gastric cancer; in concordance with this, overexpression of KLF4 can suppress proliferation in several epithelial cell types. Here we investigate the effects of KLF4 on pro/pre-B-cell transformation by v-Abl and BCR-ABL, oncogenes that cause leukemia in mice and humans. We show that overexpression of KLF4 induces arrest and apoptosis in the G1 phase of the cell cycle. KLF4-mediated death, but not cell-cycle arrest, can be rescued by Bcl-XL overexpression. Transformed pro/pre-B cells expressing KLF4 display increased expression of p21CIP and decreased expression of c-Myc and cyclin D2. Tetracycline-inducible expression of KLF4 in B-cell progenitors of transgenic mice blocks transformation by BCR-ABL and depletes leukemic pre-B cells in vivo. Collectively, our work identifies KLF4 as a putative tumor suppressor in B-cell malignancies.

Animals↗
PubMed2006

Durable responses to imatinib in patients with PDGFRB fusion gene-positive and BCR-ABL-negative chronic myeloproliferative disorders.

Fusion genes derived from the platelet-derived growth factor receptor beta (PDGFRB) or alpha (PDGFRA) play an important role in the pathogenesis of BCR-ABL-negative chronic myeloproliferative disorders (CMPDs). These fusion genes encode constitutively activated receptor tyrosine kinases that can be inhibited by imatinib. Twelve patients with BCR-ABL-negative CMPDs and reciprocal translocations involving PDGFRB received imatinib for a median of 47 months (range, 0.1-60 months). Eleven had prompt responses with normalization of peripheral-blood cell counts and disappearance of eosinophilia; 10 had complete resolution of cytogenetic abnormalities and decrease or disappearance of fusion transcripts as measured by reverse transcriptase-polymerase chain reaction (RT-PCR). Updates were sought from 8 further patients previously described in the literature; prompt responses were described in 7 and persist in 6. Our data show that durable hematologic and cytogenetic responses are achieved with imatinib in patients with PDGFRB fusion-positive, BCR-ABL-negative CMPDs.

Adult↗
PubMed1995

Inhibition of chronic myelogenous leukemia cells harboring a BCR-ABL B3A2 junction by antisense oligonucleotides targeted at the B2A2 junction.

Chronic myeloid leukemia (CML) is a hematopoietic stem cell disorder characterized by the BCR-ABL hybrid gene. Two types of hybrid BCR-ABL mRNA have been found, B2A2 and B3A2. As the BCR-ABL rearrangement is specific to leukemic cells, selective inhibition of leukemic cell growth by BCR-ABL antisense oligonucleotides (ASO) has been reported in vitro for CML patients and cell lines. However, controversial results have been obtained from preclinical studies using anti-BCR-ABL ASO, as nonspecific inhibition of leukemic cell growth was evidenced in some cases. B3 exon secondary structure was deduced from its sequence and found to be a loop. According to this predictive structure of exon B3, a 56-mer antisense oligonucleotide targeting the polypurine bases from the B2A2 junction was devised which would inhibit proliferation (MTT assay) of B3A2 junction cell lines (K562 and a murine cell line Ba/F3 transfected with the B3A2 junctional sequence). This ASO had a hairpin-like secondary structure and was found to be much more resistant to the action of nucleases than control 18-mer standard oligonucleotides. Hybridization to its target mRNA occurs via formation of a triplex structure. A concentration of 5 microM of specific 56-mer B2A2 ASO was necessary to demonstrate 50% optical density (OD) reduction for K562 cell line and Ba/F3 transformed by B3A2 cDNA. Sense and non-sense 56-mer sequence or 18-mer linear ASO showed no effect for these concentrations. Western blot showed a partial inhibition of P210 protein; expression of P145abl remains unchanged. The 56-mer ASO also inhibited the proliferation of B2A2 junction cell line BV173 at the same concentration and showed no effect on the HL60 cell line used as control.

Base Sequence↗
PubMed1997

Bcr-abl translocation can occur during the induction of multidrug resistance and confers apoptosis resistance on myeloid leukemic cell lines.

Apoptosis was studied in parental and mdr-1 expressing U937, HL60 and K562 myeloid leukemic cell lines using mdr unrelated inducers of apoptosis such as Ara-C, cycloheximide, serum deprivation, ceramide, monensin and UV irradiation. Apoptosis was efficiently induced by all these treatments in U937 and HL60 cells while K562 cells exhibited an apoptosis-resistant phenotype except with UV and monensin. The pattern of apoptosis resistance in mdr-1 expressing U937 (U937-DR) and HL60 (HL60-DR100) was similar to that presented by K562. This apoptosis-resistant phenotype of mdr cells was not overcome by concentrations of verapamil inhibiting the P-gp 170 pump. The acquisition of this phenotype was posterior to the mdr-1 expressing phenotype since a HL60-DR5 variant, selected at the beginning of the induction of resistance, presented a low level of mdr-1 expression without resistance to apoptosis. The variations observed in the Fas (CD95) expression between sensitive and resistant cells were not sufficient to account for apoptosis resistance. However, a high expression in Abl antigen was found in all the apoptosis-resistant cells. RT-PCR and Western blot analysis showed that this increase in Abl antigen content was accompanied by the expression in U937-DR and HL60-DR100 cells of a hybrid bcr/abl mRNA and a 210 kD Bcr/Abl protein which was constitutive in K562. This expression was due to the translocation of abl and the amplification of the bcr-abl translocated gene. These results are in agreement with the role of Bcr/Abl tyrosine protein kinase as an inhibitor of apoptosis independently of the mdr-1 expression. They also suggest that translocation of the abl gene in the bcr region is a highly probable rearrangement in the mdr-1 expressing myeloid cells and that Bcr/Abl tyrosine kinase effect on apoptosis needs the regulation of intracellular pH and is inactive against UV-induced apoptosis.

Journal Article↗
PubMedDate not supplied

Adoptive immunotransfer with viable donor mononuclear cells for recurrent chronic myelogenous leukemia after allogeneic bone marrow transplantation in two children.

Two children with Ph+ chronic myelogenous leukemia (CML) relapsed in the chronic phase after allogeneic bone marrow transplantation (BMT). They were treated with transfusions of peripheral blood mononuclear cells (PBMC) obtained from the former bone marrow donors in combination with interferon alfa-2. In one child, CML was successfully controlled as shown by disappearance of Ph+ metaphases as well as negativity for BCR-ABL fusion gene transcripts demonstrated by polymerase chain reaction (PCR) analysis. The patient has remained in complete remission without evidence of disease for 12 months after donor PBMC transfusions. The other child showed disappearance of BCR-ABL gene transcripts by PCR analysis only in peripheral blood cells, but PCR positivity persisted in bone marrow samples. These results indicate that adoptive immunotherapy may be a further alternative in children with relapse of CML after allogeneic BMT as previously described for adult patients.

Adolescent↗
PubMed2001

[Disease-related gene and tumor progression].

Chronic myelogenous leukemia is a stem cell tumor characterized by the t(9; 22)(q34; 11) translocation generating the BCR/ABL chimeric gene. The BCR/ABL fusion gene shows several functions, including inhibition of adhesion to stroma cells and extracellular matrix, activation of mitogenic signalings, inhibition of apoptosis, and degradation of inhibitory proteins, and thereby causes transformation of hematopoietic progenitors. Among its functions, the signal transduction pathways activated by the fusion gene are Ras and MAP kinase pathways, Jak-Stat pathways, PI3 kinase pathways, and Myc pathways. Molecular mechanisms in blastic crisis remains largely unknown. However, loss of functions of tumor suppressor genes such as p53, RB, and p16, activation of oncogene Ras, overexpression of Evi-1 might be involved in disease progression.

Animals↗
PubMed2000

[Constructing a Competitor of BCR-ABL cDNA by PCR Site-Directed Mutagenesis]

A competitive mimic of the cDNA of the BCR-ABL fusion gene was constructed, and its feasibility was testified by capillary electropheresis (CE). The 4 bp-shorter mimic was obtained by PCR amplification using a newly synthesized downstream primer analogous to the former one. Mimics of both types of BCR-ABL cDNA were achieved and the validity was verified with restriction endonuclease. And the products of the coamplification PCR could be easily separated by capillary electrophorisis. The mimic can be used to quantitative detection of BCR-ABL gene through competitive RT-PCR in chronic myeloid leukemia.

Journal Article↗
PubMed1995

Induction of erythroid differentiation by 5-fluorouracil in K562 leukemia cells.

K562 cell line, established from a patient in the blast crisis of chronic myeloid leukemia, expresses high levels of c-myc and bcr/abl gene products. Exposure of K562 cells to 5-fluorouracil (5-FU) resulted in a marked benzidine-positive erythroid differentiation with concomitant reduction in cell proliferation. No change in c-myc mRNA or protein levels occurred during 96 h of drug treatment. In contrast, a biphasic change of p210bcr/abl and the abl-associated kinase activities was observed upon treatment with 5-FU. The change in p210bcr/abl expression may be mediated at the translational level, since the steady-state level and the enzymatic activity of p210bcr/abl are reduced, whereas bcr/abl mRNA levels are unaltered. The results are consistent with the existence of pleiotropic differentiation pathways in K562 cells.

Cell Differentiation↗
PubMed1992

Philadelphia chromosome-positive leukaemia: the translocated genes and their gene products.

Overwhelming evidence indicates a role for the deregulated ABL protein tyrosine kinase in the aetiology of CML and Ph-positive acute leukaemia. These disorders are characterized by the generation of BCR/ABL fusion proteins with elevated tyrosine kinase activity. Although much is known concerning the transforming potential of ABL proteins in various systems, very little is understood of the normal function and mode of regulation of ABL activity. The mechanism of oncogenic activation is therefore also obscure. In spite of this, our understanding of the molecular details of these chromosomal translocations allows the design of therapies directed against their unique, leukaemia-specific proteins and RNA products.

Abelson murine leukemia virus↗
PubMed2002

Bcr: a negative regulator of the Bcr-Abl oncoprotein in leukemia.

The fusion of 5' parts of the BCR gene to the ABL gene at the second exon yields several forms of an oncogenic Bcr-Abl oncoprotein observed in several types of Philadelphia chromosome positive leukemia patients. The first exon of the BCR gene is a critical part of this fusion, as the coiled-coil domain at the amino terminal domain of the Bcr protein causes oligomerization of the Bcr-Abl oncoprotein forming tetramers, thereby activating the tyrosine kinase activity of the normally silent c-Abl protein. Another consequence of this Bcr-Abl fusion is the extensive autophosphorylation of the cis Bcr protein sequences on tyrosine residues. This review will summarize the effects of Bcr-Abl autophosphorylation on tyrosines as they relate to the oncogenic activity of Bcr-Abl, and as a means to inactivate the serine/threonine kinase activity of the Bcr protein. The review also discusses our findings that show that phosphoserine Bcr by means of a unique structure, binds to the Abl SH2 domain of the Bcr-Abl oncoprotein, and as a result this SH2 binding inhibits the oncogenic effects of the oncoprotein. Our results indicate that one effect of this binding is inhibition of the Bcr-Abl tyrosine kinase. Serine 354 of Bcr plays a major role in this inhibition. In the case of Bcr(64-413), serine 354 is required for the formation of the unique Bcr structure that binds to the Abl SH2 domain.

Amino Acid Sequence↗
PubMed1990

Ph-negative chronic myeloid leukemia: molecular analysis of ABL insertion into M-BCR on chromosome 22.

Leukemic cells from a patient with Ph-negative chronic myeloid leukemia (CML) had a normal karyotype. M-BCR was rearranged and chromosome in situ hybridization showed an ABL insertion between 5' and 3' M-BCR on an apparently normal chromosome 22. The association of 5' BCR and 3' ABL at the 5' junction of the chromosome 9 insert was typical of that found for the BCR-ABL fusion gene in other patients with the standard t(9;22) and CML. With an M-bcr-3' probe, we cloned and characterized a 3' junction fragment. Field inversion gel electrophoresis and chromosome in situ hybridization studies using a probe isolated from genomic DNA 5' of the junction showed that 3' M-BCR was joined to a region of chromosome 9q34 rich in repetitive sequences and lying some distance 3' of ABL. The chromosome 9 insert was at least 329 kilobases long and included 3' ABL and a larger portion of chromosome 9q34. Our results allowed us to exclude transposon- or retroviral-mediated insertion of ABL into chromosome 22. Instead, we favored a two-translocation model in which a second translocation reconstituted a standard t(9;22)(q34;q11) but left the chromosome 9 insert, including 3' ABL, in chromosome 22.

Chimera↗