Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

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.
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PMID: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. 1174 71

Chronic myelogenous leukemia is a stem cell tumor characterized by the t(9; 22)(q34; 11) translocation generating the BCR/ABL chimeric gene. The BCR/ABL fusion gene shows several functions, including inhibition of adhesion to stroma cells and extracellular matrix, activation of mitogenic signalings, inhibition of apoptosis, and degradation of inhibitory proteins, and thereby causes transformation of hematopoietic progenitors. Among its functions, the signal transduction pathways activated by the fusion gene are Ras and MAP kinase pathways, Jak-Stat pathways, PI3 kinase pathways, and Myc pathways. Molecular mechanisms in blastic crisis remains largely unknown. However, loss of functions of tumor suppressor genes such as p53, RB, and p16, activation of oncogene Ras, overexpression of Evi-1 might be involved in disease progression.
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PMID:[Disease-related gene and tumor progression]. 1176 32

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

BCR/ABL fusion tyrosine kinase is responsible for the initiation and maintenance of the Philadelphia chromosome (Ph(1))-positive chronic myelogenous leukemia (CML) and a cohort of acute lymphocytic leukemias (ALL). STI571 (Gleevec), a novel anti-leukemia drug targeting BCR/ABL kinase can induce remissions of the Ph(1)-positive leukemias. STI571 was recently combined with the standard cytostatic drugs to achieve better therapeutic results and to overcome emerging drug resistance mechanisms. We decided to search for a more specific partner compound for STI571. Our previous studies showed that a signaling protein phosphatidylinositol-3 kinase (PI-3k) is essential for the growth of CML cells, but not of normal hematopoietic cells (Blood, 86:726,1995). Therefore the anti- Ph(1)-leukemia effect of the combination of BCR/ABL kinase inhibitor STI571 and PI-3k inhibitor wortmannin (WT) or LY294002 (LY) was tested. We showed that STI571+WT exerted a synergistic effect against the Ph(1)-positive cell lines, but did not affect the growth of Ph(1)-negative cell line. Moreover, the combinations of STI571+WT or STI571+LY were effective in the inhibition of clonogenic growth of CML-chronic phase and CML-blast crisis patient cells, while sparing normal bone marrow cells. Single colony RT-PCR assay showed that colonies arising from the mixture of CML cells and normal bone marrow cells after treatment with STI571+WT were selectively depleted of BCR/ABL-positive cells. Biochemical analysis of the CML cells after the treatment revealed that combination of STI571+WT caused a more pronounced activation of caspase-3 and induced massive apoptosis, in comparison to STI571 and WT alone. In conclusion, combination of STI571+WT or STI571+LY may represent a novel approach against the Ph(1)-positive leukemias.
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PMID:Phosphatidylinositol-3 kinase inhibitors enhance the anti-leukemia effect of STI571. 1218 86

The "golden path", produced by the Human Genome Project effort, is composed of a collection of overlapping and fully sequenced BAC/PAC clones covering almost completely the human genome. These clones can be advantageously exploited as fluorescence in situ hybridization (FISH) probes for the characterization of rearrangements frequently found in tumors. Breakpoint characterization can be further refined by generating additional smaller FISH probes through LONG-PCR amplification of specific DNA segments, 5-10 kb in size, using appropriate BAC/PAC probes as template. We report here an example of this approach that has been used to characterize a complex Ph-negative chronic myeloid leukemia (CML Ph-) case in which the BCR/ABL fusion gene was found located on chromosome 9.
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PMID:Molecular cytogenetic characterization of a complex rearrangement involving chromosomes 9 and 22 in a case of Ph-negative chronic myeloid leukemia. 1223 39

Change in proportion of metaphases with a Ph chromosome is often used to measure effect of treatment in chronic myelocytic leukemia, but this method requires analysis of dividing cells. Dual-color fluorescence in situ hybridization (D-FISH) analysis of bone marrow (BM) or blood (PB), can be used to establish the proportion of interphase nuclei with BCR/ABL fusion. We studied the correlation of these three measures with each other and with response classification categories. In a clinical trial to test rIFN(-) versus rIFN(-) +Ara-C (N = 65 patients), we defined for each cytogenetic and FISH parameter, the patient's "best response" over time and at any given time. The strength and nature of agreement among the three measurements were determined by regression, correlation, and kappa statistic. Correlations between cyBM versus D-FISH-BM, cyBM versus D-FISH-PB and D-FISH-BM vs. D-FISH-PB were fairly strong. Regression showed cyBM values were significantly higher than those of D-FISH-PB or D-FISH-BM. No difference between D-FISH-PB and D-FISH-BM was apparent. When numerical responses (BR%) were classified into response categories (CR, PR, MR, NR), levels of agreement were weak to moderate. We observed a trend toward disagreement between cyBM and each D-FISH method, with cyBM tending to "downgrade" response category. Whether analyzed using actual numerical values or classified into response categories, cyBM differed from D-FISH-BM or D-FISH-PB. The results indicate that mixing data of different methods to measure treatment response within or between patients may be misleading clinical index.
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PMID:Correlation of three methods of measuring cytogenetic response in chronic myelocytic leukemia. 1239 76

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


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