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PubMed2002

Several types of mutations of the Abl gene can be found in chronic myeloid leukemia patients resistant to STI571, and they can pre-exist to the onset of treatment.

Targeting the tyrosine kinase activity of BCR-ABL represents a very promising therapeutic strategy in chronic myeloid leukemia (CML). Despite strong efficacy of the tyrosine kinase inhibitor STI571, resistance has been observed in a significant proportion of patients in advanced CML stage or in Ph-positive acute lymphoid leukemia (ALL). We investigated in this study the mechanism of resistance to STI571 through point mutations in the tyrosine kinase domain and/or BCR-ABL gene amplification in 24 patients (16 in chronic phase and 8 in accelerated phase of the disease) who obtained no cytogenetic response to STI571 treatment. Screening for the already-described Thr315Ile point mutation in the ABL domain using a reverse transcription polymerase chain reaction restriction fragment length polymorphism (RT-PCR-RFLP) technique, 3 patients showed a proportion of mutated transcript at the time of resistance. The same technique failed to detect mutation at diagnosis, but a specific allele-specific oligonucleotide (ASO)-PCR on DNA for the Thr315Ile mutation and, after sequencing, for 2 newly described Phe311Leu and Met351Thr substitutions, showed the presence of rare mutated cells prior to STI571 therapy. Furthermore, the increased proportion of mutated cells during treatment detected by ASO-PCR strongly suggested clonal selection by the functional inhibiting effect of these mutations. Finally, no BCR-ABL gene amplification was detected by fluorescent in situ hybridization (FISH) in the 24 STI571-resistant patients. Our data support that in CML patients treated with STI571, ABL mutations are not restricted to the accelerated phase of the disease and that, at least in some cases, mutations seem to occur prior to STI571 therapy, probably as second mutational events during the course of CML.

Alleles↗
PubMed2001

Subgroup of patients with Philadelphia-positive chronic myelogenous leukemia characterized by a deletion of 9q proximal to ABL gene: expression profiling, resistance to interferon therapy, and poor prognosis.

A major deletion of the region proximal to the rearranged ABL gene on 9q was found in 14/94 (15%) of chronic myelogenous leukemia Philadelphia-positive patients by interphase fluorescent in situ hybridization with the BCR/ABL extra signal dual-color probe. Preliminary results indicated that the prognosis of the deletion 9q patients is probably worse than that of the non-deletion 9q patients. Twelve of the 14 deletion 9q patients were treated with alpha-interferon and none had a major cytogenetic response. The median duration of the chronic phase in patients not undergoing BMT was significantly shorter for the deletion 9q patients as compared to the non-deletion 9q patients (p =.0144). DNA microarray technology was performed in order to compare the gene expression patterns between the two groups of patients. A number of genes exhibiting differential expression, especially involving cell adhesion and migration, were identified. This finding may identify a sub-group of CML patients with different cell properties and a relatively poor prognosis.

Antineoplastic Agents↗
PubMed1993

[BCR and ABL gene rearrangement in chronic myeloid leukemia].

The fact of chromosome 9 and 22 translocation connected with the fusion of BCR and ABL genes occurring in 95% patients with chronic myeloid leukemia (CML) enables us to use molecular biology methods in CML diagnosis. By means of these methods we also can prove the rearrangement of BCR gene in some cytogenetically negative cases that are without so called Philadelphia (Ph) chromosome. 51 patients with myeloproliferative disease have been tested by Southern technique during the last year. The rearrangement of BCR gene was detected in 28 patients, in 13 of 14 patients where the Ph chromosome and also in 3 of 13 patients where the Ph chromosome was not detected. The detection of BCR gene rearrangement helped us to set the diagnosis of CML more precisely.

Chromosomes, Human, 21-22 and Y↗
PubMed1991

Normal c-abl gene protein--a nuclear component.

The subcellular distribution of the c-abl and bcr-abl gene products from KG1A and K562 cells has been studied by two different techniques. Firstly, physical disruption followed by subcellular fractionation was used to demonstrate that normal c-abl (p145) was recovered from the cytosol and the nuclear fractions of KG1A cells. In contrast, bcr-abl products were recovered exclusively from the cytosol fraction of K562 cells. Secondly, indirect immunofluorescence was used to localize c-abl protein to the cytoplasm, nuclear membrane and infrequently to the nucleus of KG1A cells and bcr-abl protein to only the cytoplasm of K562 cells. Thus both the approaches indicate that there is a component of normal c-abl products which appears to be nuclear and this is not reflected in the distribution of the bcr-abl 210 kDa protein, which remains cytosolic.

Animals↗
PubMed2002

[Detection of BCR-ABL gene sequences using RT-PCR in patients with leukemia in the IX region. Chile].

BACKGROUND: The BCR-ABL fusion gene is the molecular expression of the Philadelphia chromosome. This cytogenetic aberration is the most frequent alteration found in leukemias, which is produced by the translocation t(9;22). Two different fusion proteins are produced depending on the break point (210 kD and 190 kD). The detection of this gene has both diagnostic and prognostic importance, associated with poor prognosis in acute lymphoblastic leukemia (ALL). AIM: To detect BCR-ABL gene sequences in patients with leukemia from the IX Region of Chile. MATERIAL AND METHODS: We studied 58 patients: 5 chronic myeloid leukemia (CML), 35 ALL, 15 acute myeloid leukemia (AML) and 3 biphenotypic leukemia. The gene sequences were detected using reverse transcriptase polymerase chain reaction (RT-PCR). RESULTS: BRC-ABL gene sequences were positive in all patients with CML, 2 of 35 ALL (one child and one adult). The remaining patients were negative. We found p210 and p190 co-expression in 2 CML and 1 ALL. CONCLUSIONS: Our results are in agreement with other reports. The detection of these and other genetic alterations will allow us to have invaluable diagnostic and prognostic information from our patients with leukemia.

Acute Disease↗
PubMed1993

Direct visualization of the transposed ABL gene in a duplicated masked Ph chromosome.

In a small percentage of cases of chronic myelogenous leukemia (CML), where the Ph chromosome is masked because of highly complex translocations and sub-microscopic rearrangements, precise identification of chromosomal aberrations by routine banding techniques has been difficult. We report on a new case of CML in which a single copy of a masked Ph chromosome was duplicated during blast crisis, i.e., the karyotype was 47,XY,dir ins(22;9)(q11;q34.1q34.2),t(1;22) (q21;q11), + der (22)t(1;22)(q21;q11). The chromosome in situ suppression hybridization (CISS) technique with whole chromosome 1 and 22 specific painting probes demonstrated that 22q11-qter had been translocated to 1q21, whereas 22q11 was the recipient of 1q21-qter. Furthermore, a cosmid probe identified the location of the ABL gene on only one chromosome 9 (band q34). The other ABL gene could be detected on both derivative chromosomes 22 at band q11 which was flanked by the translocated part of the long arm of chromosome 1, thus providing direct visualization of the ABL insertion in a double masked Ph chromosome. A breakpoint within the 5.8 kb major breakpoint cluster [M-BCR] region was shown by Southern blotting.

Adult↗
PubMed1994

Detection of chimeric BCR-ABL genes on bone marrow samples and blood smears in chronic myeloid and acute lymphoblastic leukemia by in situ hybridization.

The presence of BCR-ABL fusion genes has important diagnostic and prognostic implications in chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL). The CML-specific chimeric BCR-ABL gene with a break involving the major breakpoint cluster region (M-bcr) of the BCR-gene has been detected by means of fluorescence in situ hybridization (FISH). In this study, we present a FISH protocol that allows the detection of breaks in both the major and the minor breakpoint cluster region (m-bcr). Three hybridization signals of D107F9, a yeast artificial chromosome (YAC)-derived probe spanning the breakpoint regions of the BCR gene, were indicative of the translocation events. To increase the specificity further, this probe was combined with cos-abl 8, a cosmid probe flanking the breakpoint within the ABL gene for dual-color hybridization. Samples of 21 patients with CML, the ALL-derived cell line SUP-B15, and of seven patients with Philadelphia chromosome (Ph1)-positive ALL (three of them with breakpoints within m-bcr) were examined. BCR-ABL fusion was detected in all cases with high specificity (false-positive nuclei: mean, 0.1%). On cytogenetic preparations, the percentages of BCR-ABL-positive interphase cells ranged from 53% to 91%. Comparable efficiencies were achieved on blood smears. In conclusion, hybridization with D107F9 and cos-abl 8 allows unambiguous diagnosis of BCR-ABL genes and is likely to become an important tool for the monitoring of therapies in patients with CML and ALL.

Adult↗
PubMed2005

[Acute lymphoblastic leukemias with aberrations of BCR-ABL genes].

AIM: To develop an original therapeutic strategy in Ph-positive acute lymphoblastic leukemia (ALL). MATERIAL AND METHODS: In November 2001 Hematological Research Center (HRC) initiated the study of chimeric BCR-ABL gene. During the first stage of the study (November 2001-July 2004), 18 primary ALL patients were recruited in HRC, from July 2004 to January 2005--16 patients in HRC, N.N. Burdenko Central Military Hospital, regional Samara hospital. The diagnosis of Ph-positive ALL was established in detection of translocation t(9;22) by standard cytogenetic test or fluorescent hibridization in situ with double signal (D-FISH), or by polymerase chain reaction with reverse transcription (RT-PCR). In detection of aberration of BCR-ABL gene the patients received stem hemopoietic cells, from June 2004 imatinib was added to chemotherapy in the period of induction and consolidation. RESULTS: Incidence rate of BCR-ABL-positive ALL by standard cytogenetic test and D-FISH makes up 20%, by RT-PCR--25%. Differences in chimeric transcripts detectability by different methods may be explained by different sensitivity of the methods. Complete hematological remissions were achieved in the majority of the patients (6 of 8) irrespective of imatinib administration. Achievement of molecular remission in BCR-ABL-positive ALL occurs also in standard chemotherapy but molecular remissions begin 2-4 months later than clinicohematological ones. CONCLUSION: In using imatinib combination with chemotherapy, molecular remission can be achieved simultaneously with hematological one. Long-term results will be analysed later.

Adolescent↗
PubMed1992

The bcr-abl gene in chronic myelogenous leukaemia.

The observation made over 30 years ago that the Philadelphia chromosome is present in nearly all patients with CML led to the identification of a novel fusion gene bcr-abl. In the past few years, the biochemical and biological properties of bcr-abl have been extensively explored. Bcr sequences appear to activate c-abl for transformation by binding to the SH2 domain of c-abl in an intramolecular interaction, presumably interfering with the adjacent SH3 regulatory domain. Upon introduction into bone marrow cells, bcr-abl can cause acute or chronic leukaemias in mice and can stimulate the growth of many cell types, including multipotent stem cells, in vitro. Although their growth is stimulated, these cells are not fully malignant blastic leukaemias. The molecular events that occur during the progression to blast crisis of CML remain largely undefined, but existing animal models and in vitro culture systems will be useful for identifying or testing candidate genes. The study of tyrosine kinase oncogenes in general will probably lead to the identification of relevant bcr-abl substrates. The elucidation of these molecules as well as more downstream events in the bcr-abl signalling pathway offers the hope for novel therapeutic interventions to control Philadelphia chromosome leukaemias.

Animals↗
PubMed1989

Alterations in c-abl gene methylation in cells transformed by phagocyte-generated oxidants.

DNA from 10T1/2 cells transformed by activated neutrophils was analyzed for restriction length polymorphisms (RFLPs) in cellular homologues of retroviral oncogenes, and consistent RFLPs were found in MspI sites of the c-abl gene of all PMN-transformed cell lines. MspI digests probed with c-myc, v-Ki-ras, v-Ha-ras or v-mos showed no RFLPs, and none were observed in EcoRI, PstI, HindIII, BamHI, SmaI, Sau3a, MboI, HhaI, or TaqI digests probed with v-abl. Analysis of HpaII digests supports the conclusion that c-abl RFLPs result from differential methylation of the CCGG HpaII/MspI recognition sequence. MspI RFLPs in the c-abl gene may provide markers for oxidant-related genetic injury.

Animals↗
PubMed2004

Detection of bcr-abl gene expression at a low level in blood cells of some patients with essential thrombocythemia.

The major bcr-abl fusion gene is seen as a major marker of chronic myeloid leukemia (CML). However, whether the bcr-abl transcript can be detected in patients with essential thrombocythemia (ET) is still a matter of controversy. We detected the messenger RNA expression of the bcr-abl gene using reverse transcription-polymerase chain reaction in peripheral-blood leukocytes (PBLs) from 63 patients with myeloproliferative disorders (including CML, ET, and polycythemia vera [PV]) and 51 normal, healthy volunteers. The bcr-abl transcript was detected in 4 of the 30 ET patients (13.3%), 17 of the 17 CML patients (100%), none of the 16 PV patients (0%), and 1 of the 51 normal subjects (1.9%). Compared with the normal controls, ET patients have a greater tendency to express the bcr-abl transcript in PBLs (P=.06, Fisher's exact test). Further semiquantitative analysis showed that the intensity of bcr-abl transcript expression in 4 ET patients and a normal individual was 10(3) to 10(4) times less than that in the CML patients. We conclude that the bcr-abl transcript can be detected in the PBLs of Philadelphia chromosome (Ph)-negative ET patients but that the level of expression is markedly less than that in CML patients. The clinical significance of this finding merits further investigation.

Aged↗
PubMed2006

Deletion of any part of the BCR or ABL gene on the derivative chromosome 9 is a poor prognostic marker in chronic myelogenous leukemia.

To evaluate the prognostic significance of submicroscopic deletions of the ABL or BCR gene associated with t(9;22) in chronic myelogenous leukemia (CML), we investigated the incidence of an ABL or BCR deletion on derivative chromosome 9 using fluorescence in situ hybridization (FISH). FISH was performed using the LSI BCR/ABL dual-fusion translocation probe on bone marrow cells of 86 patients with CML. Of 86 patients, ABL deletion was detected in 13 (15.1%) patients and BCR deletion in 8 patients (9.3%). Patients with ABL deletion showed shorter event-free survival time (EFS) than those without ABL deletion (P = 0.020). Patients with BCR deletion showed significantly short overall survival time (OS; P = 0.039). Patients with ABL and/or BCR deletion (14/86 patients, 16.3%) showed significantly short OS and EFS (median OS, 43.0 months; median EFS, 40.0 months), compared to the patients without any BCR or ABL gene deletions (median OS, 94.0 months; median EFS, 90.0 months; P = 0.041 for OS, P = 0.008 for EFS). All the patients with BCR deletion, except for one, had a concomitant ABL deletion, suggesting that BCR deletion occurs in conjunction with ABL deletion. In patients with ABL deletion only, BCR/ABL rearrangement with b2a2 mRNA type tended to be more frequent than in patients without any deletion of the two genes (P = 0.073). Deletion of any of the BCR or ABL genes on derivative chromosome 9 was associated with both short OS and EFS. We conclude that deletion of not only the ABL gene, but also of the BCR gene, is a poor prognostic marker that indicates rapid disease progression in CML.

Acute Disease↗
PubMed1986

Overlapping cDNA clones define the complete coding region for the P210c-abl gene product associated with chronic myelogenous leukemia cells containing the Philadelphia chromosome.

The Philadelphia chromosome, observed in greater than 90% of patients with chronic myelogenous leukemia, results from a reciprocal translocation between chromosomes 9 and 22. The translocation breakpoint on chromosome 9 occurs near the ABL gene and correlates with the production of a chronic myelogenous leukemia-specific 8.5-kilobase ABL-related mRNA species accompanied by a structurally altered ABL protein (P210c-abl). The N-terminal sequence of the protein is derived from the BCR gene on chromosome 22. We have isolated overlapping cDNA clones from the K-562 cell line corresponding to approximately 8.5 kilobases of mRNA and have sequenced 2550 nucleotides at the 5' end. Our results indicate that the 5' end of the 8.5-kilobase mRNA consists of greater than 400 nucleotides of noncoding sequence that are greater than 80% G + C rich. Based on our sequence analysis, we propose that initiation of translation occurs at nucleotide 471, such that the initial 927 amino acids of P210c-abl are derived from BCR sequences. Our cDNA clones thus define the complete coding sequences for the P210c-abl gene product.

Base Sequence↗
PubMed2001

Competitive polymerase chain reaction as a method to detect the amplification of bcr-abl gene of chronic myeloid leukemia.

BACKGROUND AND OBJECTIVES: The chimeric product of the bcr-abl rearranged gene is critical in the pathogenesis of chronic myeloid leukemia (CML), yet its role in the progression of the disease remains unclear. There is some evidence that increased bcr-abl expression levels, possibly due to gene amplification, precede the clonal evolution of CML hematopoietic progenitors toward a fully transformed phenotype and might be involved in their resistance to interferon-alpha or tyrosine kinase inhibitors. DESIGN AND METHODS: To quantify the bcr-abl gene both at the genomic and at the transcriptional levels we developed a competitive polymerase chain reaction (PCR) strategy. The competitive PCR technique is based upon the co-amplification of the sample template (target) together with increasing amounts of a DNA fragment (competitor) sharing with the target the primer recognition sites, but differing in size. We constructed a competitor for the quantification of both b2a2 and b3a2 alternative splicing forms of the bcr-abl chimera and established the accuracy and reproducibility of our competitive strategy in a clone of the murine 32DG hematopoietic cell line (32D LG7), which bears a stable integration of a single copy of p210 bcr-abl fusion gene. We utilized this technique to follow, over a period of 200 days, the fusion gene copy numbers and transcription rates in several p210 bcr-abl-transduced 32D cell clones, an experimental condition mimicking the evolution of CML myeloid progenitors in vivo. RESULTS: Our results are consistent with p210 bcr-abl overexpression but not gene amplification associated with their clonal evolution. Increased p210 bcr-abl transcription rate is associated with the abrogation of radiation-induced apoptotic cell death, suggesting a role for the chimeric gene expression level in cell life expectancy after a genotoxic insult. INTERPRETATION AND CONCLUSIONS: We conclude that the assessment of gene amplification and expression might serve to improve prognostic classification and follow-up of CML patients.

Alternative Splicing↗
PubMed2000

Detection of molecular variants of BCR-ABL gene in bone marrow and blood of patients with chronic myeloid leukemia by reverse-transcriptase polymerase chain reaction (RT-PCR).

Very limited data exists in Thailand regarding the frequency of BCR-ABL leukemic gene and its prognostic implication in Thai CML patients. The objective of this study was to develop a rapid molecular assay for the detection of the two most commonly reported variants of BCR-ABL fusion gene, B2A2 and B3A2 in CML patients. Bone marrow or peripheral blood were used for RNA extraction and reverse-transcribed to cDNA for PCR amplification. 92 per cent of CML patients (91/99) were positive for BCR-ABL gene (61% B3A2 and 31% B2A2). 8/99 CML patients were BCR-ABL-negative. B3A2 and B2A2-positive patients did not have any different clinical and hematological features at presentation although B3A2 patients tended to be slightly older and had higher platelet counts. 71/71 non-CML including other MPD and leukemia cases were all negative for BCR-ABL gene. In conclusion, a rapid RT-PCR assay has now been developed for the detection of this hallmark gene in CML patients. It should be of great value in the differential diagnosis of CML from other diseases. Long-term follow-ups of CML patients with different variants are needed to determine the prognostic importance of each gene variant.

Adult↗
PubMed1997

The chimeric BCR-ABL gene.

The 1982 discovery that in chronic myeloid leukaemia (CML) the ABL proto-oncogene is translocated to the BCR gene located on chromosome 22 initiated many studies on the structural organization and function of these genes. The nucleotide sequence of the entire BCR and major parts of the ABL gene has now been determined. However, the actual cause of the fusion of BCR with ABL remains essentially unknown. Mouse models have been helpful to unravel the normal cellular function of BCR and ABL, as well the activity of BCR-ABL, although a single mechanism explaining the transforming activity of the latter has not been discovered. The cause of progression of the disease remains unknown, and no single genetic abnormality has been linked to the blast phase of CML. Much has been learned concerning the molecular biology of CML, but answers to the fundamental questions above may be expected in the coming years in parallel to increasing knowledge of genome structure, signal transduction and cell cycle control.

Animals↗
PubMed1993

Rearrangements of c-myc and c-abl genes in tumour cells in Burkitt's lymphoma.

Rearrangements of oncogenes c-myc and c-abl were detected by non-radioactive hybridisation in a case of Burkitt's lymphoma/leukaemia. The surface phenotype of Burkitt's cells were positive for CD19, CD20, HLA-DR, CD14, CD33 and surface immunoglobulin markers. Although cytogenetic analysis was not performed, the c-myc and heavy immunoglobulin genes had the same 14.2 kilobase EcoRI molecular size fragment, suggesting a possible t(8;14) translocation which is a common marker of this malignancy. The c-abl oncogene was also rearranged in DNA digested BamHI and EcoRI. The physiopathological implications of the rearranged c-abl gene are unknown, this being the first case, as for as is known, of Burkitt's lymphoma/leukaemia with a rearranged c-abl gene.

Blotting, Southern↗