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Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chronic myeloid leukaemia (CML) is caused by the product of the BCR-ABL oncogene, located on the Philadelphia (Ph) chromosome. BCR-ABL is generated as a result of a reciprocal t(9;22) chromosomal translocation. The mechanisms responsible for this illegitimate recombination event remain elusive but are presumed to require a close spatial association of the translocation partners (chromosomes 9 and 22). BCR-ABL fusion transcripts can be detected by a sensitive reverse transcription-polymerase chain reaction (RT-PCR) in the leucocytes of some healthy individuals suggesting that chromosomal translocations may occur frequently in the general population. The presence of BCR-ABL fusion transcripts does not imply that the individual will inevitably develop CML since other conditions must be favourable for expansion of the abnormal clone. Breakpoints in the ABL gene occur within a 5' segment. BCR-ABL fusion transcripts lack ABL exon a1 and consist of BCR exons fused directly to ABL exon a2. The breakpoints in the BCR gene on chromosome 22 are found within three defined regions. Depending on the position of the BCR breakpoint, fusion genes are generated that encode 190-, 210- or 230-kD forms of the Bcr-Abl tyrosine kinase. Since the ABL component of the fusion gene is largely invariant, it follows that variability in disease phenotype may be due to protein sequences encoded by the translocation partner, BCR. Different disease phenotypes are associated with each of the three Bcr-Abl oncoproteins, p190(Bcr-Abl), p210(Bcr-Abl )and p230(Bcr-Abl). Mechanisms associated with malignant transformation include altered cellular adhesion, activation of mitogenic signalling pathways, inhibition of apoptosis and proteasomal degradation of physiologically important cellular proteins. CML is subject to an inexorable progression from an 'indolent' chronic phase to a terminal blast crisis. Disease progression is presumed to be associated with the phenomenon of genomic instability.
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PMID:Cytogenetic and molecular genetic aspects of chronic myeloid leukaemia. 1243 15

We describe a case of Philadelphia chromosome-positive chronic myeloid leukemia (Ph-positive CML) expressing p190(BCR-ABL). Reverse transcription-polymerase chain reaction (RT-PCR) analysis of bone marrow cells showed a 472-bp band using primers specific for the p190(BCR-ABL) but not p210(BCR-ABL) transcript. Sequencing analysis revealed that the PCR product was derived from the fusion between BCR exon e1 and ABL exon a2 (e1a2). CML expressing p190(BCR-ABL) is relatively rare. In a review of the literature, it may be grouped into 2 categories; approximately half of the patients exhibited prominent monocytosis and intermediate hematological phenotype between CML and chronic myelomonocytic leukemia, and the remaining patients showed no monocytosis.
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PMID:Philadelphia chromosome-positive chronic myeloid leukemia expressing p190(BCR-ABL). 1252 Nov 92

We developed and extensively validated a real-time PCR assay for the quantitation of bcr-abl to determine residual disease in patients with chronic myelogenous leukemia. This method quantitates the p210 and the p190 bcr-abl RNA fusion transcripts with results normalized to a housekeeping gene, using the 5'-exonuclease technique and the ABI PRISM 7700 Sequence Detection System (Applied Biosystems, Foster City, CA). We parallel tested 372 clinical specimens and 50 peripheral blood samples from patients not known to have any myeloproliferative disorders. The results were 100% specific. Sensitivity studies showed that this method can detect bcr-abl in cell lines diluted to 0.0001% and can detect a single bcr-abl plasmid spiked into negative RNA. The between-run reproducibility showed a coefficient of variance (CV) of 12.3%, and within-run reproducibility showed a CV of 13.8%. This method can be used to reliably monitor the disease load in patients with bcr-abl-positive diseases.
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PMID:Comprehensive validation of a real-time quantitative bcr-abl assay for clinical laboratory use. 1286 71

BCR/ABL associated leukemias are characterized by a high degree of chromosomal and genomic instability. The genomic instability is usually associated with disease progression, as in chronic myelogenous leukemia or a poor prognosis as observed in hallmark Philadelphia chromosome-positive acute lymphoblastic leukemia. It is unclear whether the phenotype of genomic instability is a primary consequence of Bcr/Abl expression or if it is secondarily acquired in the multistep process of tumor evolution. To address this issue, we measured the frequency of insertions and deletions in P190(BCR/ABL) transgenic mice. These mice ubiquitously express Bcr/Abl for an average of 3 months before developing B-cell type lymphoma/leukemia. Genome scanning for insertions and deletions in samples of DNA extracted from kidney and spleen tissues taken from preleukemic animals was performed using the inter-simple sequence repeat PCR. We observed an increased frequency of insertions and deletions in the tissues of preleukemic animals, which could be partially reversed with the c-Abl specific inhibitor STI571. These results suggest that the expression of Bcr/Abl can directly induce a mutator phenotype that antedates overt neoplastic transformation, and that STI571 appears to be capable of reversing this effect.
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PMID:Measurement of genomic instability in preleukemic P190BCR/ABL transgenic mice using inter-simple sequence repeat polymerase chain reaction. 1294 12

The p210(bcr-abl) and p190(bcr-abl) fusion proteins, respectively responsible for chronic myelogenous leukemia and acute lymphoblastic leukemia, present deregulated tyrosine kinase activity and abnormal localization. The Dbl homology domain of Bcr, activating Rho GTPases, is present in p210(bcr-abl), but absent in p190(bcr-abl). We investigated the interaction of Bcr-Abl chimeras and Rho proteins by coimmunoprecipitation, pull-down experiments and GEF activity measurement. RhoA, Rac1 and Cdc42 interact in vivo with p210(bcr-abl) only. Moreover, the three types of GTPases are activated in vitro and in vivo by p210(bcr-abl). Nevertheless, Rac1 and Cdc42, but not RhoA, are activated by p190(bcr-abl) in vitro and in vivo. Part of this GEF activity of p190(bcr-abl) is probably attributable to p95(vav), which is complexed with both p190(bcr-abl) and p210(bcr-abl) in an activated form. p160(bcr), also in complex with Bcr-Abl, presents no GEF activity in p190(bcr-abl)-expressing cells. These results suggest that differential activation of Rho proteins should play a major role in Bcr-Abl-induced leukemogenesis.
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PMID:Differential interaction and activation of Rho family GTPases by p210bcr-abl and p190bcr-abl. 1450 24

Treatment of chronic myelogenous leukemia with a specific inhibitor of the Bcr/Abl tyrosine kinase, imatinib, has shown great promise. However, acute lymphoblastic leukemias that express Bcr/Abl only transiently respond to imatinib. Therefore, alternative treatments for this type of leukemia are urgently needed. Here, we examined the activity of the farnesyltransferase inhibitor SCH66336 as a single chemotherapeutic agent in a nude mouse model representative of very advanced stage Bcr/Abl P190-positive lymphoblastic leukemia/lymphoma. Our results show that oral administration of the inhibitor was able to significantly increase the survival of these mice compared to controls treated with vehicle (P<0.005), and caused marked regression of the tumor burden in the treated mice. Upon prolonged treatment, lymphomas re-emerged and a subset of cells from two of such lymphomas tested was able to survive in the presence of increased concentrations of SCH66336. The same cells, however, remained sensitive towards imatinib. A combination of the two drugs, preceded by a therapy to reduce the initial tumor burden, could be very effective in the treatment of Ph-positive ALL. We conclude that SCH66336, on its own, is remarkably effective in eradicating large numbers of lymphoblastic lymphoma cells and causing visible reduction in tumor size, with minimal toxicity.
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PMID:A farnesyltransferase inhibitor increases survival of mice with very advanced stage acute lymphoblastic leukemia/lymphoma caused by P190 Bcr/Abl. 1460 39

Chronic myelogenous leukemia is characterized by the presence of the reciprocal t(9;22)(q34;q11) in which c-abl located on chromosome 9, and the bcr locus located on chromosome 22, are disrupted and translocated creating a novel bcr-abl fusion gene residing on the derivative chromosome 22. In most cases, the breakpoint in abl occurs within intron 1. Depending on the breakpoint in bcr, exon 2 of abl (a2) joins with exons 1 (e1), 13 (b2), or 14 (b3), or rarely to exon 19 (e19) of bcr resulting in chimeric proteins of p190, p210 and p230, respectively. Currently, several multiplex real-time reverse transcriptase-polymerase chain reaction (RT-PCR)-based assays for detecting bcr-abl are available to assess the levels of the three common fusion transcripts, b2a2, b3a2 and e1a2. Although these assays circumvent the requirement for individual fusion sequence quantitative polymerase chain reaction-based assays, they do not identify the specific fusion transcript. Knowledge of the latter is useful to rule out false-positive results and to compare clones before and after therapy. We designed a novel multiplex real-time RT-PCR assay to detect bcr-abl that allows accurate quantification and determination of the specific fusion transcript. In this assay, abl primer labeled at its 5' end with the fluorescent dye NED (Applied Biosystems) is incorporated into the bcr-abl fusion product during amplification. The NED fluorescent dye in abl primer, without interfering with fluorescent TaqMan probe signal, allows subsequent identification of the fusion transcript by semiautomated high-resolution capillary electrophoresis and GeneScan analysis.
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PMID:TaqMan RT-PCR assay coupled with capillary electrophoresis for quantification and identification of bcr-abl transcript type. 1465 55

Patients with Philadelphia chromosome-positive (Ph(+)) acute lymphoblastic leukemia (ALL) generally have a poor prognosis and would benefit from the development of new therapeutic approaches. We previously demonstrated that an allosterically controllable ribozyme, maxizyme (Mz), can induce apoptosis in chronic myelogenous leukemia (CML) cells. Ph(+) ALL cells harbor a bcrabl fusion gene (e1a2) encoding a 190-kDa fusion protein (p190) involved in disease pathogenesis. In this study, we have designed a Mz that specifically cleaves e1a2 mRNA and transduced this e1a2Mz into Ph(+) ALL cells using a third-generation lentiviral vector system. In 3 of 5 Ph(+) ALL cell lines, e1a2Mz transduction resulted in a significant decrease in viability and increased cell apoptosis. We observed a decrease in e1a2 mRNA in all Ph(+) ALL cells transduced with e1a2Mz, and the e1a2 mRNA level was higher in e1a2Mz-resistant cells than in e1a2Mz-sensitive cells. All samples of primary Ph(+) ALL cells tested showed e1a2Mz-induced growth inhibition and apoptosis. Importantly, e1a2Mz did not influence the colony formation of normal CD34(+) cord blood cells. These results indicate that e1a2Mz kills Ph(+) ALL cells specifically, suggesting that it may be used as a novel gene therapy strategy for Ph(+) ALL.
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PMID:A novel maxizyme vector targeting a bcr-abl fusion gene induced specific cell death in Philadelphia chromosome-positive acute lymphoblastic leukemia. 1503 77

The diagnosis of chronic myeloid leukemia is based on detection of the Philadelphia (Ph) chromosome or the BCR-ABL gene. The junction present in the transcript may vary according to the reciprocal translocation t(9;22)(q34;11). Identification of the transcript (p190, p210 or p230) does not reveal the type of junction but this information is very important for classification of patients in clinical trials. Most identification kits do not explore p230 transcripts and are unable to determine exotic breakpoints. We have developed a clinical molecular diagnosis assay, able to identify all of the BCR-ABL transcripts and, by single assay, to characterize all of the possible transcript junctions. This technique is based on RT-PCR and PCR-capillary electrophoresis. For each patient sample, we performed RT-PCR with three different BCR primers each coupled to a specific different fluorochrome and a unique reverse ABL primer. Depending on the transcript, only one BCR primer was used for each RT-PCR. After capillary electrophoresis and fluorescence determination, we were able to identify both the transcript and its junction at the same time.
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PMID:Characterization of the different BCR-ABL transcripts with a single multiplex RT-PCR. 1550 73

Progress in understanding the molecular basis of signal transmission and transduction has contributed substantially to clarifying the mechanisms of leukemogenesis and of leukemia progression and has led to the identification of a number of specific molecular targets for treatment. Chronic myeloid leukemia (CML) has provided one of the best models, as the identification of a leukemia-specific hybrid tyrosine kinase (BCR-ABL, p210, p190) has led to the identification and the successful therapeutic application of a powerful tyrosine kinase inhibitor, imatinib. The BCR-ABL fusion gene is the result of a reciprocal translocation between the long arms of chromosomes 9 and 22, t(9;22)(q34;q11), which characterizes more than 95% of the cases of CML. The resulting chimeric proteins (P210 and P190), which retain a constitutively activated tyrosine kinase activity, have a causative role in the genesis of the leukemia process. In agreement with this observation, BCR-ABL tyrosine kinase inhibitors have recently emerged as powerful new therapeutic tools, obtaining extraordinary results in early chronic-phase CML as well as in more advanced phases of the disease. Although these results represent a remarkable breakthrough, there are still numerous issues, such as the emergence of resistance, that remain unsolved and that will need further investigation. In spite of its low incidence, CML remains a paradigmatic model for understanding the pathogenesis and therapeutic options of human leukemias.
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PMID:Rational approaches to the design of therapeutics targeting molecular markers: the case of chronic myelogenous leukemia. 1565 Feb 67


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