Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The BCR/ABL fusion gene is pathognomonic for chronic myelogenous leukaemia (CML). We have previously reported alternative splicing of BCR/ABL, as indicated by the detection of both p190- and p210-encoding transcripts, in about 60% of CML patient samples. These exon-skipping events involved the joining of ABL exon 2 to variable upstream BCR exons. Similarly, ABL exon 2 is alternatively spliced to either of two upstream ABL exons (1a or 1b) in c-ABL. We have constructed BCR and BCR/ABL minigenes to study this phenomenon in more detail. These constructs were transfected into various cell types and splicing was assessed by reverse transcriptase PCR. Whereas the basic BCR minigene expressed exon-inclusive transcripts only, insertion of genomic DNA spanning ABL exon 2 induced exon-skipping but only when expressed in the CML cell lines K562 and EM3. In this study we localized the required sequence element to ABL exon 2 itself. These results mimic the splicing phenotype displayed by most CML patients. We propose a model where a trans-factor present in some CML cells interacts with ABL exon 2 pre-mRNA to promote skipping of upstream BCR exons.
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PMID:Exon-skipping in BCR/ABL is induced by ABL exon 2. 1079 14

Reverse transcription-polymerase chain reaction (RT-PCR) was used to study 34 patients with chronic myelogenous leukemia (CML) associated with negative Philadelphia (Ph) chromosome. This report showed evidence of a chimeric BCR/ABL transcript in 18 (52.9%) and 28 (82.4%) cases by first PCR and seminested PCR, respectively. In these BCR/ABL transcript positive cases, the incidence of BCR exon3/ABL exon2 (B3A2) and BCR exon 2/ABL exon2 rearrangement was 25 (89.3%) and 3 (10.7%) cases, respectively. The other 6 Ph negative patients showed no evidence of reciprocal translocation of BCR to chromosome 9. This data demonstrates that seminested PCR is sufficiently sensitive to detect BCR/ABL fusion transcript in Ph chromosome negative CML patients.
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PMID:BCR/ABL rearrangement in Philadelphia chromosome negative CML patients. 1086 10

The t(9;22)(q34;q11) produces the BCR/ABL fusion gene which codifies a 210 kb protein with a strong tyrosine kinase activity and is involved in cellular development and growth. Because this translocation is a reciprocal event, it could give rise to a second fusion gene, ABL-BCR, on the derivative 9q+. We analyzed the influence of the 3' M-BCR deletion on the clinical picture at diagnosis and disease outcome in 57 patients with a clinical diagnosis of CML. Molecular studies were done on DNA from peripheral blood leukocytes or bone marrow with the restrictions enzymes BglII, EcoRI, HindIII, and BamHI, and the BCR 3' probe (transprobe 1) (Oncogene Science Inc.), which encompasses almost all of the 5.8 Kb of the M-BCR gene area. In 18 patients Southern blot analysis showed deletion of the 3' end of BCR gene (32.7%). There were no significant differences between patients with or without deletion, either in the clinical and laboratory data at the disease diagnosis or at the disease outcome. The absence of differences between the patients with and without 3' BCR deletion supports the hypothesis that the hybrid gene ABL-BCR does not have an important role in leukemogenesis in CML cases.
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PMID:Deletion of BCR region 3' in chronic myelogenous leukemia. 1167 77

Chromosomal translocation t(9; 22)(q34; q11), found in 95% of patients with chronic myeloid leukemia(CML) and 30% of adult patients with acute lymphoblastic leukemia (ALL) generates a chimeric gene, BCR/ABL. There are three kinds BCR/ABL fusion transcripts of p210BCR-ABL found in CML and ALL, p190BCR-ABL mainly in ALL, and p230BCR-ABL in CML, either of which depends on the location of the breakpoints within the BCR gene. For the detection of t(9; 22) or BCR/ABL, karyotype analysis, Southern blot hybridization of the BCR gene, fluorescence in situ hybridization, and reverse transcription-polymerase chain reaction(RT-PCR) have been used. Especially, recent advance in RT-PCR methods have allowed refined quantitative detection of the BCR/ABL transcripts, which are useful for monitoring response status and detecting minimal residual disease.
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PMID:[Genetic diagnosis of chronic myeloid leukemia]. 1176 35

Constitutive activation of tyrosine kinases, such as the BCR/ABL fusion associated with t(9;22)(q34;q22), is a hallmark of chronic myeloid leukemia (CML) syndromes in humans. Expression of BCR/ABL is both necessary and sufficient to cause a chronic myeloproliferative syndrome in murine bone marrow transplantation models, and absolutely depends on kinase activity. Progression of CML to acute leukemia (blast crisis) in humans has been associated with acquisition of secondary chromosomal translocations, including the t(7;11)(p15;p15) resulting in the NUP98/HOXA9 fusion protein. We demonstrate that BCR/ABL cooperates with NUP98/HOXA9 to cause blast crisis in a murine model. The phenotype depends both on expression of BCR/ABL and NUP98/HOXA9, but tumors retain sensitivity to the ABL inhibitor STI571 in vitro and in vivo. This paradigm is applicable to other constitutively activated tyrosine kinases such as TEL/PDGFbetaR. These experiments document cooperative effects between constitutively activated tyrosine kinases, which confer proliferative and survival properties to hematopoietic cells, with mutations that impair differentiation, such as the NUP98/HOXA9, giving rise to the acute myeloid leukemia (AML) phenotype. Furthermore, these data indicate that despite acquisition of additional mutations, CML blast crisis cells retain their dependence on BCR/ABL for proliferation and survival.
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PMID:A murine model of CML blast crisis induced by cooperation between BCR/ABL and NUP98/HOXA9. 1203 33

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.
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PMID:BCR/ABL p210, p190 and p230 fusion genes in 250 Mexican patients with chronic myeloid leukaemia (CML). 1206 77

Short 21-mer double-stranded RNA (dsRNA) molecules have recently been employed for the sequence-specific silencing of endogenous human genes. This mechanism, called RNA interference (RNAi), is extremely potent and requires only a few dsRNA molecules per cell to silence homologous gene mRNA expression. We used dsRNA targeting the M-BCR/ABL fusion site to kill leukemic cells with such a rearrangement. Transfection of dsRNA specific for the M-BCR/ABL fusion mRNA into K562 cells depleted the corresponding mRNA and the M-BCR/ABL oncoprotein. This was demonstrated by real-time quantitative PCR and Western blots. The BCR/ABL knockdown was accompanied by strong induction of apoptotic cell death. Leukemic cells without BCR/ABL rearrangement were not killed by M-BCR/ABL-dsRNA. In addition, to corroborate the extraordinary sequence specificity of RNAi, we designed another RNA oligo matching the M-BCR/ABL fusion site but having two point mutations within its central region. We show that these two point mutations abolished both p210 reduction and induction of apoptosis in K562 cells. Finally, we compared leukemic cell killing by RNAi to that caused by the ABL kinase tyrosine inhibitor, STI 571, Imatinib. For full induction of apoptosis, dsRNA targeting M-BCR/ABL required 24 h more than Imatinib. This may be caused by the relatively long half-life of the BCR/ABL oncoprotein, which is not targeted by the RNAi mechanism, but is affected by STI 571. When we applied ds M-BCR/ABL RNA and STI 571 in combination, we did not observe a further increase in the induction of apoptosis. Nevertheless, these data may open a field for further studies towards gene-therapeutic approaches using RNA interference to kill tumor cells with specific genetic abnormalities.
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PMID:Killing of leukemic cells with a BCR/ABL fusion gene by RNA interference (RNAi). 1217 41

We present two patients with Ph-negative chronic myeloid leukemia (CML) and fusion signal BCR/ABL on both chromosomes 9, located in region 9q34. The first case was a 27 years old man with CML. Molecular studies (RT-PCR) revealed the rearrangement in the major-BCR region and expression of chimeric BCR/ABL mRNA of b3a2 configuration. By classical cytogenetic studies (G-banding) karyotype 46,XY was found in short-term cultivated bone marrow cells and phytohemagglutinin (PHA) stimulated peripheral lymphocytes. FISH studies revealed the BCR/ABL fusion signals on both chromosomes 9 and green BCR signals on both chromosomes 22 in all mitoses studied. Detection of the alleles of ABL1 intragenic STR locus by fluorescence PCR followed by fragmentation analysis in the patient and his parents provided no information about transmission of the ABL gene. Quantitative assessment of BCR/ABL transcript level by RT-PCR showed 60 and 70% BCR/ABL positivity in two peripheral blood samples at 6,5 and 10,5 months after diagnosis, respectively, which does not correspond to the expression from two identical BCR/ABL hybrid genes. Therefore, the possible mechanism of the origin of two BCR/ABL fusion signals present on both chromosomes 9 could not be resolved and remains speculative. The second case was a 53 years old male with diagnosis of chronic phase of CML, with first sign of acceleration one month after diagnosis and death because of sepsis in blastic phase within four months. The cytogenetic findings were identical to those in case No. 1., i.e. karyotype 46, XY by G-banding, two BCR/ABL fusion signals on both chromosomes 9 and RT-PCR molecular studies proved b3a2 breakpoints. It is generally accepted that prognosis of the patients with fused BCR/ABL gene located on chromosome 9 is poor. The presence of two fused genes could be anticipated as two Ph chromosomes in accelerated and blastic phases of the disease. However, in our study, quantitative findings of BCR/ABL transcripts did not corresponded to the expression of two BCR/ABL genes originating from duplication. If this assumption is correct then the expression of both fused genes BCR/ABL was in case No. 1 equally suppressed and total expression reached about the level of one BCR/ABL gene.
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PMID:Location of the BCR/ABL fusion genes on both chromosomes 9q34 in Ph negative chronic myeloid leukemia. 1240 Jun 16

STI571 is a specific ABL family tyrosine kinases inhibitor approved for treatment of leukemias. It can differentially modulate the action of other antileukemic drugs. We have recently shown that deregulation of the mechanisms of DNA damage and repair in BCR/ABL-positive cells may be involved in drug resistance of these cells, and thus determine the response of cancer cells to therapy. In the present work we investigated DNA damage and repair induced by idarubicin in the presence of STI571 and amifostine, a normal cell protector, in the BCR/ABL fusion tyrosine kinase-expressing cell line. Amifostine increased the viability of both kinds of cells in the absence of STI571, but had no effect in the presence of the inhibitor. STI571 did not change the response of both BCR/ABL-expressing cells and their control counterparts to idarubicin in terms of DNA damage and repair. However, the presence of amifostine modulated the response of the cells. In the absence of STI571 amifostine decreased the DNA-damaging effect of idarubicin in normal cells and increased it in BCR/ABL-positive cells. STI571 at 2 M abolished the protective effect of amifostine against idarubicin in normal cells and diminished the magnitude of the amifostine-induce increase in cancer cells. These results suggest that amifostine should be applied with special caution in idarubicin-based chemotherapies of BCR/ABL-positive leukemias involving STI571 inhibitor.
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PMID:DNA damage and repair in BCR/ABL-expressing cells after combined action of idarubicin, STI571 and amifostine. 1243 39

We present a patient with a Philadelphia chromosome positive (Ph+) acute lymphocytic leukaemia (ALL) refractory to standard induction chemotherapy. Treatment with the ABL-specific tyrosine kinase inhibitor STI571 (Glivec, Gleevec, imatinib mesylate) resulted in a complete haematologic and cytogenetic remission. Allogeneic stem cell transplantation from an unrelated donor could be undertaken while the patient was in STI571-induced complete remission from the leukaemia. At present, the patient has a 15-month post-transplantation follow-up and is in stable molecular remission as evaluated by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) for the BCR/ABL fusion gene transcript. Our case demonstrates that STI571 can act as a bridge to potentially curative allogeneic stem cell transplant in otherwise poor prognosis Ph+ ALL.
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PMID:Favorable outcome with STI571 (imatinib mesylate) and allogeneic stem cell transplantation in a case of Ph+ chemorefractory acute lymphocytic leukaemia. 1247 93


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