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PubMed1996

Molecular demonstration of BCR/ABL fusion in two cases with chronic myeloproliferative disorder carrying variant Philadelphia t(14;22)(q32;q11).

We report two cases with chronic myeloproliferative disorder which were found to carry simple variant Philadelphia (Ph) t(14;22)(q32;q11) in unstimulated bone marrow mononuclear cells. Both cases were characterized molecularly by Southern blot, reverse transcription-polymerase chain reaction (RT-PCR), and direct sequencing of the RT-PCR products. In the first case (female, aged 65, in blastic transformation which developed one year after the initial diagnosis of myelofibrosis), a t(14;22) (q32;q11) was found in association with several other chromosomal abnormalities [48,XX,+X,+5,del(5) (q12q32),+8,der(9)t(9;11)(q32;q11),-11]; molecular analysis demonstrated the presence of a BCR-ABL chimeric gene and mRNA transcript of the b2-a2 type. In the second case (female, aged 16, with clinical and hematologic features typical of chronic myelogenous leukemia in chronic phase), a t(14;22) (q32;q11) was identified as the sole karyotypic abnormality; again, molecular analysis demonstrated the presence of a BCR-ABL chimeric gene and mRNA transcript, this time of the b3-a2 type. Our findings further support the notion that, even when undetectable by conventional cytogenetics, band 9q34 participates in all Ph chromosomes and leads to the formation of chimeric BCR-ABL genes.

Adolescent↗
PubMed1995

Establishment and characterization of a new Ph1-positive chronic myeloid leukemia cell line MC3 with trilineage phenotype and an altered p53 gene.

A new Ph1-positive leukemic cell line (MC3) expressing the P210bcr/abl oncoprotein was established from a patient with CML in blast crisis. The MC3 cells showed the trilineage phenotype of myeloid, lymphoid (CD19) and megakaryocytoid lineages, and had a proliferative response to rhIL-1 and rhIL-3 in the serum-free culture. These results and the expression of CD34 indicated that the MC3 cells have characteristics of hematopoietic progenitor cells. Recently, it has been documented that alterations of the p53 gene in leukemic cells are frequently detected during the blast crisis of CML. The MC3 cells contained the altered p53 gene. In addition, the original leukemic cells showed the point-mutational activation of the N-ras gene and an additional chromosomal abnormality inv(3q), but the MC3 cells contained no such abnormalities, indicating that not all of the original leukemic cells had these abnormalities. Thus, the MC3 cell line may provide several insights into investigations of the blast crisis in CML as well as hematopoietic progenitor cells.

3T3 Cells↗
PubMed1998

The kinetics and extent of engraftment of chronic myelogenous leukemia cells in non-obese diabetic/severe combined immunodeficiency mice reflect the phase of the donor's disease: an in vivo model of chronic myelogenous leukemia biology.

In vitro studies have provided little consensus on the kinetic abnormality underlying the myeloid expansion of chronic myelogenous leukemia (CML). Transplantation of human CML cells into non-obese diabetic mice with severe immunodeficiency disease (NOD/SCID mice) may therefore be a useful model. A CML cell line (BV173) and peripheral blood cells collected from CML patients in chronic phase (CP), accelerated phase (AP), or blastic phase (BP) were injected into preirradiated NOD/SCID mice. Animals were killed at serial intervals; cell suspensions and/or tissue sections from different organs were studied by immunohistochemistry and/or flow cytometry using antihuman CD45 monoclonal antibodies (MoAbs), and by fluorescence in situ hybridization (FISH) for the BCR-ABL fusion gene. One hour after injection, cells were sequestered in the lungs and liver, but 2 weeks later they were no longer detectable in either site. Similar short-term kinetics were observed using 51Cr-labeled cells. The first signs of engraftment for BV173, AP, and BP cells were detected in the bone marrow (BM) at 4 weeks. At 8 weeks the median percentages of human cells in murine marrow were 4% (range, 1 to 9) for CP, 11% (range, 5 to 36) for AP, 38.5% (range, 18 to 79) for BP, and 54% (range, 31 to 69) for BV173. CP cells progressively infiltrated BM (21%) and spleen (6%) by 18 to 20 weeks; no animals injected with the cell line or BP cells survived beyond 12 weeks. The rate of increase in human cell numbers was higher for BP (7.3%/week) as compared with CP (0.9%/week) and AP (0. 5%/week). FISH analysis with BCR and ABL probes showed that some of the human cells engrafting after injection of CP cells lacked a BCR-ABL gene and were presumably normal. We conclude that CML cells proliferate in NOD/SCID mice with kinetics that recapitulate the phase of the donor's disease, thus providing an in vivo model of CML biology.

Animals↗
PubMed1986

v-abl activates embryonic globin gene expression in mouse erythroleukemia cells.

The Philadelphia chromosome translocation, which is present in 90-95% of chronic myelogenous leukemia patients, involves translocation of the c-abl protooncogene to chromosome 22 and is accompanied by activation of embryonic globin gene expression in the K562 chronic myelogenous leukemia cell line. To test directly if the protein products of the translocated c-abl protooncogene can activate embryonic globin gene expression, we transfected the v-abl oncogene (which shares the property of autophosphorylation with the translocated c-abl protooncogene) into mouse erythroleukemia cells. v-abl-transfected mouse erythroleukemia cells, which contained multiple copies of the v-abl transgenome, exhibited activation of mouse embryonic globin gene expression. These results suggest that the translocated c-abl protooncogene of the Philadelphia chromosome translocation is central to the pathogenesis of chronic myelogenous leukemia and that it may result in the activation of embryonic globin genes in some chronic myelogenous leukemia cell lines.

Abelson murine leukemia virus↗
PubMed1992

Expression of the mouse c-abl type IV proto-oncogene product in the insect cell baculovirus system.

The cellular gene c-abl is the normal homologue of the transforming gene (v-abl) within the genome of the Abelson leukaemia virus. The cDNA sequence coding for the cellular form of the murine abl gene (c-abl type IV) has been inserted into the baculovirus transfer vector, pAc36C, so that the c-abl gene is under the control of the polyhedrin promoter of Autographa californica nuclear polyhedrosis virus (AcNPV). Spodoptera frugiperda cells infected with the recombinant transfer vector in the presence of wild type AcNPV DNA yielded recombinant, polyhedrin negative virus that expressed moderate levels of the c-Abl protein (representing approx. 0.5-1% of the stained cellular proteins as determined by densitometric scanning). The insect derived c-Abl protein was compared to the P210-BCR/ABL protein from K562 cells, a cell line derived from a patient with chronic myelogenous leukaemia. Antibodies raised against synthetic peptides based on c-abl encoded peptides react with the insect derived c-Abl. In addition, the baculovirus derived c-Abl protein has a tyrosine kinase activity as demonstrated by phosphorylation of a synthetic polypeptide and also by autophosphorylation. Phosphoamino acid analysis of immunoprecipitated, autophosphorylated baculovirus derived c-Abl protein indicates that the majority of label incorporated is on the tyrosine residues. Immunofluorescence microscopy has been used to show that the majority of the c-Abl protein expressed in cells infected with recombinant virus is located in the nuclear and plasma membranes.

Animals↗
PubMed2001

Effect of a selective Abl tyrosine kinase inhibitor, STI571, on in vitro growth of BCR-ABL-positive acute lymphoblastic leukemia cells.

By employing a new semi-quantitative assay system that includes co-culturing leukemia cells with the mouse bone marrow-derived stromal cell line MS-5, we examined the suppressive effect of a selective inhibitor of ABL tyrosine kinase, STI571, on acute lymphoblastic leukemia (ALL) cells with BCR-ABL fusion. Leukemic blast cells from eight patients with B-precursor ALL, including three patients with BCR-ABL-positive ALL, were cultured on monolayers of MS-5 cells for 3 weeks with or without addition of variable amounts of STI571. In all cases, cobblestone areas (CAs) were formed, showing clear linear cell dose-dependent curves, allowing quantitative assessment of blast cell growth. The progenitor frequencies obtained by this direct CA-forming cell (CAFC) assay were equivalent to ALL progenitor frequencies assessed by the standard limiting dilution assay. The number of CAFCs ranged from 12.3 to 140.3/10(4) cells. In BCR-ABL-positive ALL patients, CA-containing cells were examined by FISH, and all contained BCR-ABL fusion genes. STI571 inhibited CA formation of BCR-ABL-positive ALL cells virtually 100% at 0.1-1.0 micromol/l. None of the five BCR-ABL-negative ALL patients showed this growth inhibition by STI571 at 0.1-1.0 micromol/l. Our results indicate that STI571 selectively inhibits in vitro growth of BCR-ABL-positive ALL cells.

Adolescent↗
PubMed1994

Differential complementation of Bcr-Abl point mutants with c-Myc.

A complementation strategy was developed to define the signaling pathways activated by the Bcr-Abl tyrosine kinase. Transformation inactive point mutants of Bcr-Abl were tested for complementation with c-Myc. Single point mutations in the Src-homology 2 (SH2) domain, the major tyrosine autophosphorylation site of the kinase domain, and the Grb-2 binding site in the Bcr region impaired the transformation of fibroblasts by Bcr-Abl. Hyperexpression of c-Myc efficiently restored transformation activity only to the Bcr-Abl SH2 mutant. These data support a model in which Bcr-Abl activates at least two independent pathways for transformation. This strategy may be useful for discerning signaling pathways activated by other oncogenes.

Adaptor Proteins, Signal Transducing↗
PubMed1996

Transcription factors: regulators of gene expression in normal and pathological states.

Initiation of transcription is the major control point for gene expression. The protein factors regulating transcription, the transcription factors, are modular proteins with distinct domains responsible for different functions including DNA binding, ligand binding, nuclear localization, and protein-protein interactions. Abnormal transcription has been associated with various human diseases from neoplasia to birth defects. These can result from chromosomal translocation or transcription factor genes (e.g. Burkitt's lymphoma) or by inappropriate activation of these factors due to synthesis of fusion genes (e.g. BCR-ABL fusion gene in Philadelphia positive leukaemia). More recently, abnormalities in transcription factor genes have been linked to such human birth defects as Waardenburg syndrome, vesicoureteral reflux and craniosynostosis.

Congenital Abnormalities↗
PubMed1998

Establishment and characterization of a retinal Müller cell line.

PURPOSE: Primary cultures of Müller cells have proven useful in cell biologic, developmental, and electrophysiological studies of Müller cells. However, the limited lifetime of the primary cultures and contamination from non-neural cells have restricted the utility of these cultures. The aim of this study was to obtain an immortalized cell line that exhibits characteristics of Müller cells. METHODS: Primary Müller cell cultures were prepared from retinas of rats exposed to 2 weeks of constant light. Cells were immortalized by transfection with simian virus 40. Single clones were obtained by repeatedly passaging cells using cloning wells. Immunocytochemical and immunoblotting studies were carried out with glial fibrillary acidic protein (GFAP)-specific and cellular retinaldehyde-binding protein (CRALBP)-specific antibodies. Transient transfections with CRALBP-luciferase constructs were performed by electroporation. RESULTS: Oncogene transformation resulted in the establishment of a permanent cell line that could be readily propagated. Immunocytochemical and immunoblotting studies demonstrated that the Müller cell line, rMC-1, expressed both GFAP, a marker for reactive gliosis in Müller cells, and CRALBP, a marker for Müller cells in the adult retina. Transient transfection assays showed that promoter-proximal sequences of the CRALBP gene were able to stimulate reporter gene expression in rMC-1. CONCLUSIONS: Viral oncogene transformation has been successfully used to isolate a permanent cell line that expresses Müller cell phenotype. The rMC-1 cells continue to express both induced and basal markers found in primary Müller cell cultures as well as in the retina. The availability of rMC-1 should facilitate gene expression studies in Müller cells and improve our understanding of Müller cell-neuron interactions.

Animals↗
PubMed1987

Heterogeneity in expression of the bcr-abl fusion transcript in CML blast crisis.

The 9;22 Philadelphia chromosome translocation in chronic myelogenous leukemia (CML) generates a bcr-abl fusion gene which codes for an aberrant 8-kb bcr-abl hybrid message. CML blast crisis cell lines display enhanced in vitro expression of this aberrant bcr-abl transcript when compared with fresh CML chronic phase cells. We directly compared in fresh patient samples the level of expression of the bcr-abl transcript in CML blast crisis versus chronic phase cells. All chronic phase patients displayed relatively low amounts of this aberrant transcript, while four of 10 blast crisis patients expressed this transcript at significantly higher levels. The remaining six blast crisis samples exhibited low levels of the aberrant transcript comparable to chronic phase cells. The two patients displaying the highest levels of the bcr-abl transcript did not harbor amplified copies of the bcr-abl fusion gene. This heterogeneity in the level of expression of the bcr-abl transcript in CML blast crisis indicates that enhanced expression of this aberrant transcript is not an absolutely necessary condition for blast transformation.

Adult↗
PubMed2002

In vitro resistance of leukaemic blasts to prednisolone in bcr-abl positive childhood acute lymphoblastic leukaemia.

BACKGROUND & OBJECTIVES: Although the outcome of children with acute lymphoblastic leukaemia (ALL) has improved dramatically over the last decade, some children still fare poorly and relapses are seen. The sensitivity of leukaemic cells to corticosteroids has emerged as an important prognostic factor in ALL. The t(9,22) translocation, resulting in the bcr-abl fusion gene, is a non-random translocation found in B-lineage acute lymphoblastic leukaemia. It is also known to be an independent poor prognostic factor for long-term disease free survival. We studied the association between the presence of bcr-abl fusion gene and in vitro prednisolone resistance in children with B-lineage acute lymphoblastic leukaemia at diagnosis. METHODS: A total of 23 children (aged 1-16 yr, median age: 12 yr) with B-lineage acute lymphoblastic leukaemia at diagnosis were included in the study. The presence of bcr-abl fusion gene was determined by reverse transcriptase-polymerase chain reaction (RT-PCR) and the in-vitro resistance to prednisolone was measured by short term colorimetric methyl thiazol tetrazolium (MTT) assay. RESULTS: A median LD50 (lethal dose for 50% cells) for prednisolone in bcr-abl positive children (n=7) was 1.6 mg/ml (range: 0.25-5.0 mg/ml) and that of bcr-abl negative children (n=16) was 0.35 mg/ml (range 0.62-1.0 mg/ml). The median LD50 for prednisolone differed significantly between the bcr-abl positive and negative groups of children with acute lymphoblastic leukaemia (P<0.005). INTERPRETATION & CONCLUSION: This is probably the first report to show that leukaemic blasts of bcr-abl positive children with ALL are about four-fold resistant to prednisolone as compared to blasts from bcr-abl negative children. This suggests that one of the reasons for the poor prognosis of bcr-abl positive ALL could be a lower steroid sensitivity.

Adolescent↗
PubMed2002

BCR/ABL p210, p190 and p230 fusion genes in 250 Mexican patients with chronic myeloid leukaemia (CML).

There are two major forms of the BCR/ABL fusion gene, involving ABL exon 2, but including different exons of BCR gene. The transcripts b2a2 or b3a2 code for a p210 protein. Another fusion gene leads to the expression of an e1a2 transcript, which codes for a p190 protein. Another, less common fusion gene is c3a2[e19a2], which encodes a p230 protein. The incidence of one or the other rearrangement in chronic myeloid leukaemia (CML) patients varies in different reported series. This study was designed to determine the frequency of coexpresion of the p210, p190 and p230 transcripts in 250 Mexican patients with CML. We performed nested and multiplex reverse transcriptase polymerase chain reaction (RT-PCR) on bone marrow samples from adult patients and found that all cases were positive for some type of BCR/ABL rearrangement. In 226 (90.4%) patients it was p210, while the remaining 9.6% showed coexpression or one of the transcripts of p190/p210/p230. In 7% of patients with p210 expression there are both isoforms (b3a2/b2a2), presumably the result of alternative splicing. The rate of coexpression of the p190/p210 transcripts was 5%, which is much lower than in other reports. This may be due to the technical factors. These patients had high platelet counts, marked splenomegaly and chromosomal abnormalities in addition to Ph'. Other types of coexpression seen were p210/p230 and p190/p210/p230, in patients with high-risk clinical factors. Our study confirms the occurrence of coexpression of different BCR/ABL transcripts, although the rate (9.6%) was much lower than has been reported in other populations. This may reflect either the sensitivity of the detection techniques used or the possibility of genetic differences between the populations studied. Coexpression may be due to alternative splicing or to phenotypic variation, with clinical courses different from classical CML.

Adolescent↗
PubMed2005

Assessment of a new RNA stabilizing reagent (Tempus Blood RNA) for minimal residual disease in onco-hematology using the EAC protocol.

Standardization efforts of real time quantitative PCR (RQ-PCR), such as the Europe Against Cancer (EAC) protocol, are actually essential. However, all the stages of the preanalytical phase (blood collection, conservation and procedures of cellular separation) which influence the ex vivo expression of many genes are not controlled. Various kits for stabilizing the RNA at the time of blood collection were developed: PAXgene Blood kit (Qiagen) and the new Tempus Blood RNA kit (Applied Biosystems). PAXgene Blood was already validated to monitor minimal residual disease (MRD) in onco-hematologic pathologies. In order to evaluate the Tempus Blood RNA kit, it was compared to unstabilized EDTA blood/Ficoll/TRIzol protocol and PAXgene Blood kit. The RNAs extracted by the different methods were assessed for quantity, quality and detection of control genes (GUS and ABL) and fusion gene transcripts BCR-ABL and TEL-AML1 by RQ-PCR. Our study shows that using the EAC protocol, the new Tempus Blood RNA kit allows the detection of fusion gene transcript with the same sensitivity as the two other protocols. Altogether, our data suggest the possible use of such a technology for MRD follow-up in myeloproliferative diseases and acute leukemias. So, further multicentric studies on leukemic patients should be performed to validate this technique in these applications.

Cell Line, Tumor↗
PubMed1988

Long-range mapping of the Philadelphia chromosome by pulsed-field gel electrophoresis.

The Philadelphia chromosome (Ph1) of chronic myelogenous leukemia (CML) contains sequences from chromosome 9, including the ABL protooncogene, that have been translocated to the breakpoint cluster region (bcr) of chromosome 22, giving rise to a bcr-ABL fusion gene, whose product has been implicated in the genesis of CML. Although chromosome 22 translocation breakpoints in CML virtually always occur within the 5.8-kilobase (kb) bcr, chromosome 9 breakpoints have been identified within the known limits of ABL in only a few instances. For a better understanding of the variability of the breakpoints on chromosome 9, we studied the CML cell line BV173. Using pulsed-field gel electrophoresis (PFGE), large-scale maps of the t(9;22) junctions were constructed. The chromosome 9 breakpoint was shown to have occurred within an ABL intron, 160 kb upstream of the v-abl homologous sequences, but still 35 kb downstream of the 5'-most ABL exon. bcr-ABL and ABL-bcr fusion genes were demonstrated on the Ph1 and the 9q+ chromosomes, respectively; both of these genes are expressed. These results suggest that the 9;22 translocation breakpoints in CML consistently occur within the limits of the large ABL gene. RNA splicing, sometimes of very large regions, appears to compensate for the variability in breakpoint location. These studies show that PFGE is a powerful new tool for the analysis of chromosomal translocations in human malignancies.

Chromosome Mapping↗
PubMed1996

Chromatin nucleoprotein complexes containing tightly bound c-abl, p53 and bcl-2 gene sequences: correlation with progression of chronic myelogenous leukemia.

We previously developed a technique to isolate subchromatin nucleoprotein complexes (NPC) that contain tightly bound genes and enzymatic activities. NPC fractions (NPCF) were prepared by directly treating isolated nuclei with MspI to generate six NPCF (S1, M1, S2, M2, 0.1K and R). The NPCF have been used to predict the potential efficacy of interferon-alpha (IFN-alpha) treatment in patients with chronic myelogenous leukemia (CML) [Nicolson et al., Gene 159 (1995) 105-111]. Here the NPCF were probed for the presence of tightly bound c-abl, p53 and bcl-2 genes. We found that the NPCF isolated from the nuclei of leukocytes of normal individuals rarely contained detectable quantities of tightly-bound c-abl, p53 or blc-2 genes or gene sequences, whereas in CML nuclei these genes were often found in tight association with multiple NPCF. Examination of NPCF isolated from the leukocyte nuclei from patients with highly progressive CML for the presence of the three genes revealed that more NPCF contained the three tightly-bound genes than leukocyte NPCF from patients with stable or less progressed CML. These data suggest that as CML progresses to more malignant states, oncogenes, suppressor genes and apoptosis-associated genes become tightly associated with NPCF.

Adult↗
PubMed2001

Fusion of the BCR and the fibroblast growth factor receptor-1 (FGFR1) genes as a result of t(8;22)(p11;q11) in a myeloproliferative disorder: the first fusion gene involving BCR but not ABL.

Constitutive activation of tyrosine kinases as a consequence of chromosomal translocations, forming fusion genes, plays an important role in the development of hematologic malignancies, in particular, myeloproliferative syndromes (MPSs). In this respect, the t(9;22)(q34;q11) that results in the BCR/ABL fusion gene in chronic myeloid leukemia is one of the best-studied examples. The fibroblast growth factor receptor 1 (FGFR1) gene at 8p11 encodes a transmembrane receptor tyrosine kinase and is similarly activated by chromosomal translocations, in which three alternative genes-ZNF198 at 13q12, CEP110 at 9q34, and FOP at 6q27-become fused to the tyrosine kinase domain of FGFR1. These 8p11-translocations are associated with characteristic morphologic and clinical features, referred to as "8p11 MPS." In this study, we report the isolation and characterization of a novel fusion gene in a hematologic malignancy with a t(8;22)(p11;q11) and features suggestive of 8p11 MPS. We show that the breakpoints in the t(8;22) occur within introns 4 and 8 of the BCR and FGFR1 genes, respectively. On the mRNA level, the t(8;22) results in the fusion of BCR exons 1-4 in-frame with the tyrosine kinase domain of FGFR1 as well as in the expression of a reciprocal FGFR1/BCR chimeric transcript. By analogy with data obtained from previously characterized fusion genes involving FGFR1 and BCR/ABL, it is likely that the oligomerization domain contributed by BCR is critical and that its dimerizing properties lead to aberrant FGFR1 signaling and neoplastic transformation.

Aged↗
PubMed2003

Molecular mechanisms of transformation by the BCR-ABL oncogene.

The BCR-ABL oncogene is generated by the Philadelphia chromosome (Ph) translocation, fusing the BCR gene to the ABL gene. The BCR-ABL fusion protein has elevated ABL tyrosine kinase activity that is critical for transformation of hematopoietic cells. Chronic myelogenous leukemia (CML) cells transformed by BCR-ABL show reduced growth factor requirements and apoptosis, as well as enhanced viability and altered adhesion. The elevated ABL kinase activity leads to chronic activation of signaling pathways that are required for all aspects of transformation. Progression of the disease from chronic phase to blast crisis correlates with additional cytogenetic alterations that are likely to contribute to the failure of traditional therapy. This review describes molecular mechanisms that are thought to be important for transformation by the BCR-ABL oncoprotein and points at pathways for targeted drug development in the treatment of CML.

Cell Transformation, Neoplastic↗
PubMed1999

ABL1 methylation is a distinct molecular event associated with clonal evolution of chronic myeloid leukemia.

Methylation of the proximal promoter of the ABL1 oncogene is a common epigenetic alteration associated with clinical progression of chronic myeloid leukemia (CML). In this study we queried whether both the Ph'-associated and normal ABL1 alleles undergo methylation; what may be the proportion of hematopoietic progenitors bearing methylated ABL1 promoters in chronic versus acute phase disease; whether methylation affects the promoter uniformly or in patches with discrete clinical relevance; and, finally, whether methylation of ABL1 reflects a generalized process or is gene-specific. To address these issues, we adapted the techniques of methylation-specific PCR and bisulfite-sequencing to study the regulatory regions of ABL1 and other genes with a role in DNA repair or genotoxic stress response. In cell lines established from CML blast crisis, which only carry a single ABL1 allele nested within the BCR-ABL fusion gene, ABL1 promoters were universally methylated. By contrast, in clinical samples from patients at advanced stages of disease, both methylated and unmethylated promoter alleles were detectable. To distinguish between allele-specific methylation and a mixed cell population pattern, we studied the methylation status of ABL1 in colonies derived from single hematopoietic progenitors. Our results showed that both methylated and unmethylated promoter alleles coexisted in the same colony. Furthermore, ABL1 methylation was noted in the vast majority of colonies from blast crisis, but not chronic-phase CML. Both cell lines and clinical samples from acute-phase CML showed nearly uniform hypermethylation along the promoter region. Finally, we showed that ABL1 methylation does not reflect a generalized process and may be unique among DNA repair/genotoxic stress response genes. Our data suggest that specific methylation of the Ph'-associated ABL1 allele accompanies clonal evolution in CML.

Alleles↗