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PubMed2004

[Identification bcr-abl fusion gene in leukemia cells with oligonucleotide microarray].

To explore the application value of bcr-abl fusion gene deterction microarray in diagnosis, typing, choosing of treatment variant and prognosis judgment, probe for fusion gene detection was designed, oligonucleotide microarray was prepared; total RNA was extracted, reverse-transcripted and labeled by fluorescence, then cDNA was hybridized with microarray in order to detect bcr-abl fusion gene in leukemia cells. The results showed that better reaction conditions were gained by exploration of hybridizotion temperature and elution conditions, bcr-abl fusion gene in leukemia cells was detected by prepared miccroarray. In conclusion, oligonucleotide microarray is effective in detecting the fusion gene and has some unique advantages and certain clinical application value, but has some deficiency too. If microarray can be improved further, it could be used widely in the field of hematology.

Fusion Proteins, bcr-abl↗
PubMed1992

Polymerase chain reaction analysis of BCR-ABL sequences in adult Philadelphia chromosome-negative acute lymphoblastic leukemia patients.

The Philadelphia (Ph) translocation is the most common cytogenetic abnormality in adult acute lymphoblastic leukemia (ALL) and is associated with an adverse prognosis. Using polymerase chain reaction (PCR) technology we recently observed a remarkably high incidence (55%) of BCR-ABL rearrangements in adult common ALL patients. In the present study we asked whether a subset of Ph-negative cALL, similarly to Ph-negative chronic myelocytic leukemia (CML) patients, exhibit BCR-ABL transcripts. PCR analysis of 58 adult Ph-negative cALL patients, including 47 cases with a normal karyotype revealed no evidence of chimeric BCR-ABL genes. We conclude that Ph-negative BCR/ABL-positive ALL is very rare entity if existing at all.

Adult↗
PubMed1991

[Detection and localization of breakpoints within the first intron of the BCR gene in Ph1-positive leukemias].

We studied breakpoints within the first intron of the BCR gene in 28 Philadelphia (Ph1)-positive acute leukemias (AL) and one Ph1-positive chronic myelogenous leukemia (CML), which lacked rearrangement of major breakpoint cluster region. With a series of genomic probes from this intronic region, we have detected chromosomal breaks in 19 of 28 patients with Ph1-positive AL and one patient with CML. Breakpoints were all located within 30 kb region at the 3' portion of the intron, same as in the previously reported cases. Breakpoints in our cases were not limited within "bcr-2" or "bcr-3", proposed by Chen, et al., but, occurred within or near Alu sequences. Our findings suggest that breakpoints are not randomly distributed throughout this intron, but, there may be some specific sequences that facilitate the process of chromosomal translocation.

Chromosome Fragility↗
PubMed1990

Remarkably long survival of a patient with Ph1-positive chronic myeloid leukemia and 5' bcr rearrangement.

Chronic myeloid leukemia (CML) was diagnosed in a 19-year-old man in 1961, and the disease remained in chronic phase, with occasional exacerbations, for 27 years. In 1976, when the first cytogenetic analysis was performed, t(9;22)(q34;q11) was found as the sole abnormality in all mitoses. During accelerated phase in 1988, a second cytogenetic investigation showed the karyotype 45,XY,t(9;22)(q34;q11),-15,-17,+der(15) t(15;17)(p13;q11). Molecular analysis revealed a rearrangement in the 5' end of the major breakpoint cluster region (M-bcr). With the case presented here, sublocalization of the bcr breakpoint has now been undertaken in altogether five CML patients with extremely long survival. It is noteworthy that in all these cases the chromosome 22 breakpoint was located in the 5' region of the M-bcr.

Adult↗
PubMed1990

[Acquisition of Philadelphia chromosome with bcr rearrangement concomitant with transformation of refractory anemia with excess of blasts with 8 trisomy into acute myelogenous leukemia].

A case of Philadelphia (Ph1) chromosome positive acute myelogeneous leukemia (AML) following a refractory anemia with excess of blasts (RAEB) with 8 trisomy is reported. The 80-year-old man developed pancytopenia during the course of follow-up after the surgical operation of the carcinoma of the sigmoid colon and the rectum for which no irradiation therapy nor chemotherapy had been applied. The diagnosis of RAEB was made according to the diagnostic criteria proposed by FAB co-operative group. Chromosomal analysis revealed 8 trisomy in 54% of the metaphases of bone marrow cells. The remainders showed normal karyotype without Ph1 chromosome. He was on androgenic steroid and activated Vitamin D3 without significant changes in the clinical and the hematological features until 3 months later when many atypical blasts appeared in the peripheral blood. The diagnosis of AML (M2) was made. Chromosomal analysis revealed Ph1 chromosome with the typical 9;22 translocation in 100% of the examined cells. 8 trisomy was not detected any more. Southern blot analysis using bcr probe showed bcr rearrangement. He was treated with a small doses of Ara-C. There was some reduction in the number of blasts in the peripheral blood. However, he died of septicemia 2 months later. The present case indicates that Ph1 positive acute leukemia with bcr rearrangement is not necessarily considered as a blastic transformation of chronic myelogeneous leukemia and such a cytogenic abnormality can appear in a leukemic transformation of myelodysplastic syndrome.

Aged↗
PubMed1989

Further evidence that the site of the breakpoint in the major breakpoint cluster region (M-bcr) may be a prognostic indicator.

A break in chromosome 22 within the major breakpoint cluster region (M-bcr) is a characteristic of Philadelphia chromosome-positive CML. We have determined the zone of the breakpoint in 80 chronic myelogenous leukemia (CML) patients and have confirmed our previous observation that a relationship does exist between the subregion of the breakpoint within the M-bcr and the average length of the chronic phase of the disease. Patients with a 3' breakpoint have a statistically shorter chronic phase (25 months) than patients with a 5' break (55 months). Thus, a molecular analysis of the M-bcr may provide a prognostically useful indicator of the probable length of the chronic phase, although the underlying mechanism of blast transformation, and the role (if any) of the hybrid phl-abl mRNA, is still unclear.

Blast Crisis↗
PubMed1989

Southern blot analysis of Bcr, N-ras, H-ras, c-myc and myb proto-oncogenes in blast crisis of chronic myelogenous leukemia.

Proto-oncogenes were studied by Southern blotting in 12 patients with chronic myelogenous leukemia in blast crisis (CML). Cytogenetically, all cases had Philadelphia (Ph1) chromosome and 4 had additional chromosomal abnormalities including +8, +19, i(17q), double Ph1. The bcr gene was rearranged in all cases and the region of breakage points were located in the 5.8 kb Bgl II-Bam HI fragment of bcr. In a case with double Ph1 the breakage points of bcr were thought to be different from each other. We analyzed other proto-oncogenes (N-ras, H-ras, c-myc and myb) by Southern blotting, but did not find any abnormalities.

Adult↗
PubMed1987

bcr-abl RNA in patients with chronic myelogenous leukemia.

The major consequence of the formation of the Philadelphia (Ph1) chromosome characteristic of leukemia cells of patients with chronic myelogenous leukemia (CML) is fusion of c-abl and bcr genes. Using a sensitive RNase protection technique, we analyzed mRNA from a large number of CML patients. In most, we identified one or both species of bcr-abl chimeric transcripts. These two mRNAs vary in the specific bcr exon joined to abl exon II and are translated into slightly different proteins. The amounts of the fused mRNA within leukemia cells vary considerably between individuals and do not correlate with the phase of the disease.

Exons↗
PubMed1994

Characterization of a promiscuous GTPase-activating protein that has a Bcr-related domain from Caenorhabditis elegans.

Human breakpoint cluster region (bcr) gene product is a member of a group of GTPase-activating proteins that act exclusively on members of the Ras-related Rho subfamily. A complementary DNA was isolated from Caenorhabditis elegans that encoded a polypeptide of 1438 amino acid residues, CeGAP, which contains a domain with sequence similarity to the COOH-terminal segment (GTPase-activating protein region) of Bcr and other known GTPase-activating proteins of the Rho subfamily. It also contains a "pleckstrin homology" motif, present in many signaling proteins including GTPase-activating proteins and nucleotide exchange factors. The Bcr-like domain of CeGAP exhibited activity not only on members of the C. elegans and human Rho subfamily but surprisingly also on C. elegans Ras protein (let-60), human Ras, and Rab3A. CeGAP is therefore the first GTPase-activating protein acting on Ras-related proteins across different subfamilies. Together with the presence of the pleckstrin homology motif, our finding suggests a central and integrative role for CeGAP in a signaling pathway common to Ras and related proteins.

Amino Acid Sequence↗
PubMed1996

Retroviral vector design for gene therapy of cancer: specific inhibition and tagging of BCR-ABLp190 cells.

BACKGROUND: The main difficulty in providing effective treatment of patients with cancer is distinguishing between tumor and normal cells. The chimeric molecules created by cancer-associated chromosomal abnormalities (such as the BCR-ABL fusion protein) represent ideal therapeutic targets since they are unique to the disease state. A major challenge, however, is how to deliver the specific anti-tumor agent into every tumor cell. MATERIAL AND METHODS: In this report we describe the use of a novel strategy to introduce specific anti-tumor reagents into every tumor cell. It uses retroviral vectors encoding both antisense transcripts specific for the BCR-ABLp190 fusion junction (the specific anti-tumor drug) and a truncated human CD5 cDNA, which allows selection of the infected cells. In order to coexpress the antisense molecule with the truncated human CD5 gene, the picornavirus internal ribosome-entry site was incorporated in the constructs. RESULTS: When the antisense transcripts in the CD5-retroviral vector were introduced into Ba/F3+p190 cells rendered interleukin 3 (IL-3) independent by expression of the BCR-ABL sequences, the cells died upon IL-3 withdrawal, as measured by the absence of CD5-positive cells. Control Ba/F3+p210 cells infected with the same virus did not die in the absence of IL-3. CONCLUSIONS: These data suggest a novel strategy for cancer treatment which incorporates the use of a retrovirus coexpressing both a selectable surface marker and a tumor-specific agent.

Antineoplastic Agents↗
PubMed1997

P210 Bcr-Abl interacts with the interleukin-3 beta c subunit and constitutively activates Jak2.

Chronic myelogenous leukemia is a neoplasm of pluripotent hematopoietic cells. Cytokines such as interleukin-3 and granulocyte-macrophage colony-stimulating factor regulate the growth and differentiation of hematopoietic precursors. These cytokines activate two distinct signals to the nucleus. One signal is through the Ras pathway, and the second involves activation of Jak2. We demonstrated that Bcr-Abl co-immunoprecipitates with and constitutively phosphorylates the common beta c chain of the interleukin-3 (IL-3) and granulocyte-macrophage-macrophage colony-stimulating factor (GM-CSF) receptors. Our data show that formation of this complex leads to the constitutive activation of Jak2. Previously, it has been demonstrated that Bcr-Abl interacts with Grb2 and Shc, which in turn activates the Ras pathway. Thus, Bcr-Abl can activate signalling through both pathways in a factor-independent fashion.

Cell Line↗
PubMed1998

[Construction of a competitor for bcr-abl cDNA by recombinant PCR].

OBJECTIVE: Competitive PCR is a powerful method for quantification of mRNA. This study sought to construct an internal standard which can be used as a competitor for bcr-abl fusion cDNA. METHODS: Using recombinant PCR for site-directed mutagenesis. RESULTS A 240bp mimic of a 276bp fragment in b3a2 type of bcr-abl cDNA was obtained. The difference in mimic,which was verified by DNA sequencing, was a 55bp deletion of the target sequence and a 19bp insertion of exogenous unrelated sequence with a XbaI restriction site. In it, except for the inner 36bp, the mimic contained the same sequence and shared the same primer recognition sites as the target b3a2 cDNA(276bp) or as the target b2a2 cDNA(201bp). The obtained recombinant vector, named pGEM-mimic, can be used as a common competitor for either b3a2 or b2a2 type of bcr-abl cDNA. CONCLUSION: This provided a simple and reliable method for constructing an internal standard used in competitive PCR.

DNA, Complementary↗
PubMed1995

Treatment of Philadelphia-chromosome-positive human leukemia in SCID mouse model with herbimycin A, bcr-abl tyrosine kinase activity inhibitor.

The molecular basis of the Philadelphia chromosome (Ph1) is a structurally altered c-abl (bcr-abl) gene which encodes an abnormally large protein with protein tyrosine kinase activity. Herbimycin a, which effectively reduced intracellular phosphorylation by bcr-abl tyrosine kinase, preferentially inhibited the growth of Ph1-positive leukemia cell lines. Injection of Ph1-positive and -negative leukemia cell lines into mice with severe combined immunodeficiency (SCID) resulted in the death of all mice due to leukemia, although the severity of illness varied according to the cell lines used. Administration of herbimycin A significantly enhanced the survival of mice inoculated with the Ph1-positive leukemia cell lines tested but barely affected the survival of mice inoculated with the Ph1-negative leukemia cell lines tested. These results suggest that herbimycin A and related compounds may be useful for the treatment of Ph1-positive leukemia. The disease that developed using the Ph1-positive leukemia cell line NALM-20 resembled human Ph1-positive acute lymphoid leukemia. There was an inverse relationship between the survival time of mice and the number of cells inoculated. The SCID mouse-NALM-20 human leukemia chimera would be a good experimental model for screening tyrosine kinase inhibitors as therapeutic agents against Ph1-positive leukemia.

Animals↗
PubMed1994

Philadelphia-negative chronic myeloid leukaemia: detection by FISH of BCR-ABL fusion gene localized either to chromosome 9 or chromosome 22.

Dual-colour FISH has been used to study two patients with chronic myeloid leukaemia (CML) associated with a normal karyotype. Co-localization of signals from BCR and ABL cosmids was observed in interphase nuclei from both patients. In one patient, analysis of metaphase spreads showed that the 3' region of the ABL gene was deleted from one chromosome 9 and inserted into chromosome 22. In a second patient 5' BCR sequences were missing from one copy of chromosome 22, and co-localized with 3' ABL sequences on chromosome 9. These results demonstrate the molecular heterogeneity of Ph-negative CML. In addition, they illustrate the potential usefulness of dual-colour FISH on interphase nuclei for monitoring the response to treatment of patients with Ph-negative CML.

Blotting, Southern↗
PubMed2003

Philadelphia negative, Bcr-Abl positive chronic myeloid leukemia associated with pure red cell aplasia.

Pure red cell aplasia (PRCA) is a rare disorder which is associated with thymoma, viral infections and autoimmune diseases. A few cases of PRCA during the clinical course of CML have been reported and these usually terminate in blastic crisis and death, suggesting a poor prognosis. However, only one case of Philedelphia chromosome negative, Bcr-Abl positive CML associated with PRCA has been reported. Here, we present a second case report of a Philedelphia negative, Bcr-Abl positive CML associated with PRCA who was unresponsive to all the chemotherapeutic regimens. We conclude that the present case supports the idea that the development of PRCA in the course of CML may be a bad prognostic sign.

Fusion Proteins, bcr-abl↗
PubMed2005

[Analysis of sequence-tagged site in bcr and abl genes by DNA pooling and dHPLC].

To investigate the relationship between the single nucleotide polymorphism (SNPs) of the bcr and abl gene and chronic myelogeous leukemia (CML), the 9 sequence-tagged sites (STS) in bcr and abl gene were screened by DNA pooling and denaturing high performance liquid chromatography (dHPLC), and the results were varified by sequencing. The results showed that the polymorphism sites were detected in 4 out of the 9 STS fragments and there were 3 bases different from the reference sequence found in 3 fragments. In conclusion, the novel SNP in U07000 fragment shows significantly different frequencies between CML and controled people.

Chromatography, High Pressure Liquid↗
PubMed1990

[Demonstration of BCR-ABL rearrangement in a patient with apparently Ph-negative chronic myeloid leukemia of 15 years' duration].

We have studied the haematologic cytogenetic and molecular features in a patient with Ph negative CML of 15 years of evolution. Cytogenetic analysis showed a normal karyotype in different studies. Molecular study showed rearrangement within bcr region. This gene fusion between c-abl oncogene and bcr gene is typical of the Ph chromosome. These results show the usefulness of performing a molecular study in those patients with Ph negative CML.

Adult↗
PubMed1995

Analysis of the clinical relevance of the breakpoint location within M-BCR and the type of chimeric mRNA in chronic myelogenous leukemia.

It has been suggested that the breakpoint location within the M-BCR segment of chromosome 22 and the type of chimeric mRNA BCR/ABL (b2a2 or b3a2) are associated with differences in the clinical and hematological characteristics of chronic myelogenous leukemia (CML). To assist in clarifying this matter, in a series of Ph-positive CML patients the relationship of both the breakpoint location within M-BCR (n = 71) and the type of chimeric mRNA BCR/ABL (n = 40) with the chronic phase duration, patients' survival, and thrombopoietic activity was analyzed. Median survival for patients with breakpoints in zones 1+2+3 (n = 38) and zones 4+5 (n = 31) was 62 and 75 months, respectively, the difference being not significant; patients with breaks in zones 1+2 (n = 19) and zones 3+4+5 (n = 50) had a median survival of 50 and 67 months, respectively (P also not significant). Moreover, no significant differences were found in the survival of patients with b2a2 (n = 16) and b3a2 (n = 24) mRNA junctions. Finally, no differences were observed in the platelet or megakaryocyte counts between patients with breakpoints in extremes 5' and 3' nor between patients with b2a2 and b3a2 mRNA. The above results are in agreement with those reported in most recent studies, confirming the lack of clinical relevance of molecular pattern in CML.

Adolescent↗