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PubMed2004

The Abl-related gene (Arg) requires its F-actin-microtubule cross-linking activity to regulate lamellipodial dynamics during fibroblast adhesion.

Microtubules (MTs) help establish and maintain cell polarity by promoting actin-dependent membrane protrusion at the leading edge of the cell, but the molecular mechanisms that mediate cross-talk between actin and MTs during this process are unclear. We demonstrate that the Abl-related gene (Arg) nonreceptor tyrosine kinase is required for dynamic lamellipodial protrusions after adhesion to fibronectin. arg-/- fibroblasts exhibit reduced lamellipodial dynamics as compared with wild-type fibroblasts, and this defect can be rescued by reexpression of an Arg-yellow fluorescent protein fusion. We show that Arg can bind MTs with high affinity and cross-link filamentous actin (F-actin) bundles and MTs in vitro. MTs concentrate and insert into Arg-induced F-actin-rich cell protrusions. Arg requires both its F-actin-binding domains and its MT-binding domain to rescue the defects in lamellipodial dynamics of arg-/- fibroblasts. These findings demonstrate that Arg can mediate physical contact between F-actin and MTs at the cell periphery and that this cross-linking activity is required for Arg to regulate lamellipodial dynamics in fibroblasts.

Actin Cytoskeleton↗
PubMed1999

Paediatric myelodysplastic syndrome (MDS) and juvenile chronic myelogenous leukaemia (JCML) detected by cytogenetic and FISH techniques.

This report presents two rare cases, one of paediatric myelodysplastic syndrome (MDS) and the other juvenile chronic myeloid leukaemia (jCML). In the first case, there were clinical and biological features of MDS-refractory anaemia with excess blasts (RAEB). The bone marrow (BM) karyotype demonstrated a monosomy 7 which was confirmed by fluorescence in situ hybridization (FISH). In addition, FISH analysis showed that an alpha-satellite DNA sequence had been transferred from chromosomes 13/21 to one homologue of chromosomes 22. The BCR-ABL rearrangement was negative. In the second case, at diagnosis, the karyotype was 46,XX. FISH analysis with the simultaneous and individual application of abl and bcr probes for chromosome 9 and 22, respectively, revealed the presence of the BCR-ABL rearrangement in addition to an extra ABL sequence locating chromosome 20. A clone that was BCR-ABL gene rearrangement negative but with an extra ABL DNA sequence on chromsome 20, and another clone that was BCR-ABL gene rearrangement negative were detected by DC-FISH and uni-colour (UC-) FISH analysis. No monosomy 7 was detected by conventional cytogenetic or FISH analyses.

Cytogenetic Analysis↗
PubMed1995

The first intron of the BCR gene contains two minor alternative exons.

In Philadelphia chromosome (Ph1) positive leukemias, the BCR gene is fused to the ABL gene. The resulting chimeric BCR-ABL oncoproteins are thought to play a central role in the pathogenesis of these diseases. We previously described two exons that can be spliced alternatively to the second BCR exon in place of the first exon to form minor messages. In this paper, we localize the alternative exons to a 4.1 kb BglII fragment in the 5' region of the large first intron of the BCR gene. This genomic structure is of interest because of its analogy to the organization of the ABL gene and because this part of the gene is not affected by the breakpoints occurring in Ph1-positive acute lymphoblastic leukemia (ALL). Using the reverse transcriptase-polymerase chain reaction (RT-PCR), we detected the alternative messages in all cases of chronic myelogenous leukemia (CML) tested, including seven samples in the chronic phase, five in the accelerated phase and nine in the acute phase, as well as in the majority of other samples studied. These findings suggest a functional role for the variant transcripts.

Base Sequence↗
PubMed2004

Existence of leukemic clones resistant to both imatinib mesylate and rituximab before drug therapies in a patient with Philadelphia chromosome-positive acute lymphocytic leukemia.

Imatinib mesylate and rituximab are molecularly targeted drugs against the BCR-ABL fusion protein and the CD20 antigen, respectively. Although these drugs have excellent anticancer effects, a major concern is drug resistance. We have investigated the case of a patient with Philadelphia chromosome-positive and CD20+ acute lymphocytic leukemia who acquired resistance to imatinib and rituximab. Imatinib therapy resulted in prompt cytogenetic remission, but resistance developed shortly thereafter. Sequencing of the kinase domain of the ABL gene and allele-specific polymerase chain reaction analysis revealed a point mutation resulting in an E255V substitution that was present before the therapy. After the patient received mild chemotherapy followed by rituximab administration, hematologic and cytogenetic remission was sustained for 5.5 months. The recurrent leukemic cells after the rituximab therapy showed not only the E255V mutation in the ABL gene but also loss of the CD20 antigen due to impaired transcription of the CD20 gene. The results of 2-color flow cytometry analysis showed that a small population of CD20(-) leukemic cells existed before the imatinib therapy. These results suggest that leukemic subclones carrying a genetic perturbation of the targeted molecules for both imatinib and rituximab were present before the therapies. The preexistence of primary resistant clones suggests the inability of combination therapy with 2 molecularly targeted drugs to overcome drug resistance in leukemia.

Aged↗
PubMed1990

Induction of a chronic myelogenous leukemia-like syndrome in mice with v-abl and BCR/ABL.

The v-abl gene in Abelson virus induces pre-B-cell lymphoma in mice while the BCR/ABL oncogene is associated with chronic myelogenous leukemia and some cases of acute lymphocytic leukemia in humans. Understanding the mechanisms by which these oncogenes affect various cell types has been hampered by a paucity of experimental systems that reproduce the range of biological effects associated with them. We have developed an experimental system in which murine hematopoietic stem cell populations are infected with either v-abl or BCR/ABL retroviruses and are used to reconstitute lethally irradiated mice. Irrespective of the form of activated abl, greater than 90% of the animals reconstituted with such cells develop tumors. About 50% of them develop a myeloproliferative syndrome that shares several features with the chronic phase of chronic myelogenous leukemia; the remaining animals succumb to pre-B-cell lymphomas. The myeloproliferative syndrome is characterized by large numbers of clonally derived, infected myeloid cells. This model will allow study of the mechanism by which activated abl genes affect hematopoietic precursors in chronic myelogenous leukemia. Furthermore, our results demonstrate that introduction of an activated abl gene into the appropriate target cell, not the structure of the gene, is the major determinant in myeloid cell specificity.

Abelson murine leukemia virus↗
PubMed1997

A rapid RT-PCR based method for the detection of BCR-ABL translocation.

AIMS: To optimise a one step reverse transcriptase polymerase chain reaction (RT-PCR) protocol for BCR-ABL chimaera detection. METHODS: Compared with published RT-PCR procedures, this novel approach has at least two advantages. First, the same enzyme is used for both reverse transcription and PCR. Second, amplification of the target (BCR-ABL chimaera) and control gene (ABL) is performed simultaneously in the same tube. RESULTS: On testing 40 chronic myelogenous leukaemia patients and 10 healthy donors there was a specificity for the newly developed technique. In addition, dilution experiments demonstrated that the protocol was highly sensitive. CONCLUSIONS: The suggested one step PCR strategy is a simple and reliable way to reveal BCR-ABL chimaeras.

DNA-Directed RNA Polymerases↗
PubMed2000

Evaluation of RNA isolation methods and reference genes for RT-PCR analyses of rare target RNA.

Reverse transcription polymerase chain reaction (RT-PCR) analysis is increasingly becoming part of the diagnostic and prognostic evaluation for hematologic and oncologic disorders. Currently, different RNA isolation methods are used in the diagnostic laboratories. No data are available on their suitability for sensitive detection of breakpoint cluster region-abelson (BCR-ABL) gene transcripts. We have extracted RNA from mononuclear cell (MNC) fractions and from lysed blood samples of 4 patients (1 with leukocytosis, 1 with chronic myelogeneous leukemia (CML) under interferon treatment, and 2 CML patients after bone marrow transplantation) with 3 RNA isolation reagents (TRIzol, RNAzol, FastTube reagent). RNA yield was slightly higher with RNAzol than with TRIzol as indicated by agarose gel electrophoresis and spectrophotometric measurement at 260 nm. The FastTube reagent was unsuitable for RNA isolation from MNC, and was not evaluated for lysed blood. Quantitative competitive RT-PCR amplification of the ABL gene showed comparable results for RNA isolated with RNAzol and TRIzol. In RNA samples extracted from lysed whole blood, the presence of amplifiable RNA/cDNA was confirmed by amplification of 4 selected reference genes (porphobilinogen deaminase (PBGD), ABL, the gene spanning the BCR on chromosome 22 and retinoic acid receptor alpha (RARA)) in a multiplex PCR. High quality, DNA-free RNA was obtained with RNAzol, and 1 BCR-ABL-positive (specific for translocation t [9; 221) cell among 2x10(4) normal cells was successfully detectable by single step RT-PCR. In RNA isolated with TRIzol, major contaminations with genomic DNA were observed which significantly impaired the interpretation of the results of RT-PCR analysis.

Base Sequence↗
PubMed1987

Effect of recombinant alpha-interferon on the expression of the bcr-abl fusion gene in human chronic myelogenous human leukemia cell lines.

Recent investigations have shown a therapeutic and cytogenetic response in chronic myelogenous leukemia (CML) patients treated with recombinant alpha 2-interferon (IFN alpha 2). Philadelphia chromosome-positive (and many Ph1-negative) chronic myelogenous leukemia cells transcribe a novel bcr-abl fusion mRNA which may confer a growth advantage upon these cells. We investigated the effect of IFN alpha 2 on the levels of bcr-abl transcript expression in three Ph1-positive CML cell lines, EM2, KCL22, and K562. Although IFN alpha 2 inhibited cell proliferation in all three CML cell lines, IFN alpha 2 had no effect on the level of bcr-abl mRNA expression in any of the CML cell lines. In contrast, IFN alpha 2 increased the expression of class I HLA gene products. We conclude that while the bcr-abl fusion gene and its transcript undoubtedly play key roles in the pathogenesis of CML, the antiproliferative effect of IFN alpha 2 in CML cell lines relies upon genetic mechanisms other than modulation of bcr-abl expression.

Cell Division↗
PubMed1999

Leukemia cell lines: in vitro models for the study of Philadelphia chromosome-positive leukemia.

The Philadelphia (Ph) chromosome, the main product of the (9;22)(q34;q11) translocation, is the cytogenetic hallmark of chronic myeloid leukemia (CML), a clonal myeloproliferative disorder of the hematopoietic stem cell; the Ph chromosome is also found in a sizeable portion of acute lymphoblastic leukemia (ALL) patients and in a small number of acute myeloid leukemia (AML) cases. At the molecular level, the t(9;22) leads to the fusion of the BCR gene (on chromosome 22) to the ABL gene (translocated from chromosome 9); this fusion gene BCR-ABL with its elevated tyrosine kinase activity must to be central to the pathogenesis of these disorders. Three different breakpoint cluster regions are discerned within the BCR gene on chromosome 22: M-bcr, m-bcr, and mu-bcr. Ph + leukemia cell lines are important tools in this research area. More than 20 ALL-and more than 40 CML-derived Ph + leukemia cell lines have been described. Furthermore, three Ph + B-lymphoblastoid cell lines, established from patients with Ph + ALL or CML, are available. Molecular analysis has documented BCR-ABL fusion genes in three apparently Ph chromosome-negative cell lines, all three derived from CML. Nearly all Ph + ALL cell lines have the m-bcr e1-a2 fusion gene (only two ALL cell lines have a b3-a2 fusion) whereas all CML cell lines, but one carry the M-bcr b2-a2, b3-a2 or both hybrids. The mu-bcr e19-a2 has been detected in one CML cell line. Four cell lines display a three-way translocation involving chromosomes 9, 22 and a third chromosome. Additional Ph chromosomes (up to five) have been found in four Ph + ALL cell lines and in 18 CML cell lines; though in some cell lines the extra Ph chromosome(s) might be caused by the polyploidy (tri- and tetraploidy) of the cells. Another modus to acquire additional copies of the BCR-ABL fusion gene is the formation of tandem repeats of the BCR-ABL hybrid as seen in CML cell line K-562. Both mechanisms, selective multiplication of the der(22) chromosome and tandem replication of the fusion gene BCR-ABL, presumably lead to enhanced levels of the fusion protein and its tyrosine kinase activity (genetic dosage effect). The availability of a panel of Ph + cell lines as highly informative leukemia models offers the unique opportunity to analyze the pathobiology of these malignancies and the role of the Ph chromosome in leukemogenesis.

Adult↗
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↗
PubMed2002

The effects of Bcr-Abl on C/EBP transcription-factor regulation and neutrophilic differentiation are reversed by the Abl kinase inhibitor imatinib mesylate.

The clinical progression of chronic myeloid leukemia (CML) from chronic phase to blast crisis is characterized by the increasing failure of myeloid precursors to differentiate into mature granulocytes. This study was undertaken to investigate the influence of Bcr-Abl and of the small molecule Abl tyrosine-kinase inhibitor imatinib mesylate on granulocyte colony-stimulating factor (G-CSF)-induced neutrophilic differentiation. We show that differentiation of 32Dcl3 cells into mature granulocytes is accompanied by the increased expression of the antigens macrophage adhesion molecule-1 (Mac-1) and Gr-1, of the G-CSF receptor (G-CSFR), of myeloid transcription factors (CCAAT/enhancer-binding protein-alpha [C/EBPalpha], C/EBPepsilon, and PU.1), and of the cyclin-dependent kinase inhibitor p27(Kip1). In 32Dcl3 cells transfected with the bcr-abl gene (32D(Bcr-Abl)), G-CSF did not trigger either granulocytic differentiation or the up-regulation of C/EBPalpha, C/EBPepsilon, and the G-CSFR. This could be correlated to a defect in c-Myc down-regulation. In contrast, the up-regulation of PU.1 and p27(Kip1) by G-CSF was not affected by Bcr-Abl. Importantly, incubation of 32D(Bcr-Ablwt) cells with the kinase inhibitor imatinib mesylate prior to G-CSF stimulation completely neutralized the effects of Bcr-Abl on granulocytic differentiation and on C/EBPalpha and C/EBPepsilon expression. Taken together, the results suggest that the Bcr-Abl kinase induces a reversible block of the granulocytic differentiation program in myeloid cells by disturbing regulation of hematopoietic transcription factors such as C/EBPalpha and C/EBPepsilon.

Animals↗
PubMed1998

Establishment of a cell line with variant BCR/ABL breakpoint expressing P180BCR/ABL from late-appearing Philadelphia-positive acute biphenotypic leukemia.

In acute leukemia (AL) with a late-appearing Philadelphia (la-Ph) translocation, it is unclear whether these translocations arise from the same molecular event as classical Ph translocations. In order to elucidate the molecular events of la-Ph and subsequent translocations of la-Ph leukemia, we performed molecular analysis on the complex rearrangements, in a cell line, MY, which was established from bone marrow mononuclear cells of a patient with a la-Ph acute biphenotypic leukemia. This la-Ph, expressing an acute lymphoblastic leukemia (ALL)-type BCR/ABL transcript, produces a novel P180BCR/ABL fusion protein reflecting deletion of 174 bases (58 amino acids) encoded by the a2 exon of the ABL gene. An immune complex kinase assay showed that this protein had autophosphorylation activity. Fluorescence in situ hybridization (FISH) in conjunction with G-banding analysis revealed that the initial der(9)t(9;22)(q34;q11) progressed to a der(9)(9pter-->9q34::22q11-->22q13::5q11.2 -->5q15:: 10q23-->10qter) by, first, a three-way translocation among the der(9)t(9;22)(q34;q11), chromosome 5, and the normal chromosome 22, and then a subsequent translocation with chromosome 10. Moreover, both the end-stage leukemic cells of the patient and the MY cell line had another translocation, t(X;12)(p11.2;p13). The 12p breakpoint was located near the ETV6 gene by analysis of pulsed-field gel electrophoresis, but transcription of ETV6 was unaffected. Tumorigenicity analysis indicated that an additional translocation, t(2;3)(p16;q29), may have caused a more malignant clone, because only MY cells with the t(2;3)(p16;q29) were capable of growing subcutaneously in nude mice within 40 days. The molecular events of leukemogenesis and leukemic progression in the present la-Ph AL occurred by accumulation of unique translocations. This cell line, MY, expressing a novel variant P180BCR/ABL protein with a deletion of the a2 exon of the ABL gene, may be useful for elucidating the pathophysiology of this fusion protein and for studying ETV6-related leukemogenesis and t(2;3), as well as the molecular mechanisms of the complex translocations.

Amino Acid Sequence↗
PubMed1983

The breakpoint of the Philadelphia chromosome 22 in chronic myeloid leukaemia is distal to the immunoglobulin lambda light chain constant region genes.

Somatic cell hybrids containing chromosomes from a patient with chronic myeloid leukaemia were used as a source of DNA for filter hybridizations with immunoglobulin lambda light chain constant region and c-onc probes. The results show that at least part of the human lambda constant region locus remains on the abnormal chromosome 22 (the Philadelphia chromosome) and therefore that this translocation occurs distal to these genes. Further, in the patient studied the c-abl gene has been translocated to the abnormal chromosome 22, thus creating a new genetic linkage between C lambda and c-abl genes.

Animals↗
PubMed1993

Tyrosine phosphorylation of P160 BCR by P210 BCR-ABL.

It is well established that the chimeric BCR-ABL gene formed by joining parts of the BCR and ABL genes plays a key role in the pathogenesis of Philadelphia (Ph) chromosome-positive leukemias. We report that simultaneous expression of P210 BCR-ABL and P160 BCR in simian COS-1 cells yielded stable complexes of these two proteins, and induced phosphorylation of P160 BCR on tyrosine residues in vivo. Tyrosine phosphorylation of a deletion mutant encoding 553 amino acids of BCR N-terminal sequences was also detected when it was coexpressed with P210 BCR-ABL. We propose that tyrosine phosphorylation of P160 BCR by P210 BCR-ABL and their stable physical interaction may perturb normal BCR functions and that these alterations are directly involved in the pathologic processes found in Ph chromosome-associated leukemias.

Amino Acid Sequence↗
PubMed1993

Phenotypic and molecular analysis of Ph1-chromosome-positive acute lymphoblastic leukemia cell lines.

We have established 2 Philadelphia chromosome (Ph1)-positive acute lymphoblastic leukemia (ALL) cell lines, designated PALL-1 and PALL-2, from distinct adult Ph1-positive ALL patients. PALL-1 was established in nude mice, and PALL-2 was established in culture. Both retained the Ph1 chromosome and expressed the ALL type bcr/abl chimeric mRNA containing the junction of the first exon of BCR gene (e1) and second exon of c-abl gene (a2). PALL-1 and PALL-2 expressed CD34 surface antigen which is characteristic of early hematopoietic progenitor cells. PALL-2 expressed antigens for both pre-B and early myeloid cells and had rearrangements of both the heavy chain of immunoglobulin gene and the beta chain of T-cell-receptor gene. Both PALL-1 and PALL-2 expressed detectable levels of p53 gene RNA. Polymerase-chain-reaction-single-strand conformation polymorphism (PCR-SSCP) analysis of the p53 gene showed a normal pattern of mobility in both cell lines. Taken together, the 2 cell lines had features of Ph1-positive ALL: (i) hematopoietic progenitor cells with pre-B-cell phenotype and, (ii) activation of e1-a2 type bcr/abl oncogene without alterations of p53 gene. These unique lines should provide a valuable tool for studying the pathogenesis of Ph1-positive ALL.

Adult↗
PubMed1990

Activation of murine c-abl protooncogene: effect of a point mutation on oncogenic activation.

Activation of the c-abl protooncogene occurs in Abelson murine leukemia virus, in Hardy-Zuckerman 2 feline sarcoma virus, and during the chromosomal translocations that generate BCR-ABL gene fusion products. To study the molecular mechanism involved in the c-abl activation, we have created a series of modifications in murine c-abl and assayed these constructs for oncogenic activity using the NIH 3T3 cell transformation assay. Our results show that amino-terminal deletions are sufficient for oncogenic activation of c-abl and high levels of oncogenic activities were generated by a deletion of 114 codons from the 5' end that deleted the SH3 region. A deletion of 53 codons from the 5' end (inclusive of deletions seen in Hardy-Zuckerman 2 feline sarcoma virus and BCR-ABL gene products) that retains the SH3 region of c-abl resulted in the generation of low levels of transforming activity. This transforming potential was substantially increased with the introduction of a G----A point mutation in codon 832 that is present in v-abl. The point mutation was found to affect the secondary structure and the tyrosine kinase activity of the mutant gene products.

Abelson murine leukemia virus↗
PubMed1993

The role of myc in transformation by BCR-ABL.

The BCR-ABL gene plays a central role in the pathogenesis of chronic myelogenous leukemia. Despite a detailed understanding of the regions of BCR and ABL required for transformation by BCR-ABL, little is known about the signalling pathway by which BCR-ABL causes transformation. The nuclear oncogene c-myc plays a critical role in BCR-ABL transformation. Levels of c-myc RNA are high in cells transformed by BCR-ABL, and overexpression of dominant negative forms of myc blocks transformation by BCR-ABL. These findings suggest that myc may be a useful therapeutic target in BCR-ABL-related leukemias.

Animals↗
PubMed1987

The Drosophila Abelson proto-oncogene homolog: identification of mutant alleles that have pleiotropic effects late in development.

The Abelson gene in Drosophila (abl) consists of ten exons extending over 26 kb of genomic DNA. The DNA sequence encodes a protein of 1520 amino acids with sequence homology to the human c-abl proto-oncogene product, beginning at the amino terminus and extending 656 amino acids through the region essential for tyrosine kinase activity. Mutant lesions in the abl gene were identified first by their failure to complement chromosomal deletions that overlap the abl DNA sequence and then by rescue of the mutant phenotypes with an abl minigene in transgenic flies. Elimination of abl zygotic function by mutations produces some recessive lethality at the pharate adult pupal stage, and mutant adults with reduced longevity, reduced fecundity, and an irregular pattern of retinal cells.

Alleles↗