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

Ribozymes are effective tools for the cleavage of target RNAs in a sequence-specific way. In chronic myelogenous leukemia (CML) the reciprocal translocation of chromosomes 9 and 22 results in the formation of the unique BCR/ABL fusion gene which is believed to play a crucial role in the establishment of CML. In order to decrease the BCR/ABL gene product we designed short synthetic ribozymes and analyzed their effects on the proliferation rate of K562 cells. Ribozymes proved to have a higher inhibitory potential as conventional antisense constructs of comparable nucleotide sequence.
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PMID:Cleavage of BCR/ABL mRNA by synthetic ribozymes--effects on the proliferation rate of K562 cells. 756 57

There is increasing evidence for a relationship between specific genomic alterations and the distinctive features of leukemia, including the course and the response to treatment. In Philadelphia (Ph) positive chronic myeloid leukemia (CML) the BCR/ABL fusion genes can be transcribed in at least two different mRNAs that can either include (a2b3) or exclude (a2b2) the exon 3 of the major breakpoint cluster region in chromosome 22. We identified by polymerase chain reaction the transcript type in 146 patients with Ph+ CML who were enrolled in a prospective study of treatment with alpha-interferon (alpha-IFN) for at least 1 year, and were followed for 39 to 84 months (median 60 months). The transcript was a2b3 in 84 cases (57%) and a2b2 in 62 cases (43%). A trend in favor of a2b3 cases was observed, as to the karyotypic response after 1 year of alpha-IFN treatment (39% in the a2b3 cases vs 24% in the a2b2 cases) and 5-year survival rate, that was 71% (95% CI 59-82) in a2b3 cases vs 57% (95% CI 41-73) in a2b2 cases. However, these differences were not significant, and we conclude that the identification of the transcript type by current methodology does not predict for response to alpha-IFN and for prognosis. Further studies may be required to confirm that conclusion, or to detect a true smaller difference.
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PMID:Chronic myeloid leukemia, BCR/ABL transcript, response to alpha-interferon and survival. The Italian Cooperative Study Group on Chronic Myeloid Leukemia. 756 4

A strong association between the Philadelphia chromosome (Ph1) and chronic myelogenous leukemia (CML) suggests that the Ph1 translocation plays a significant role in pathogenesis of CML. For this reason, Ph1-positive leukemias have been well studied from the molecular, clinical and cell biological perspective. In this review article, intracellular signalling events involving BCR/ABL fusion gene products are discussed in the context of the role of the Ph1 chromosome in human leukemia.
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PMID:BCR/ABL signal transduction. 759 21

We investigated leukemic cells from a patient with chronic myelocytic leukemia (CML) and a normal 46,XX karyotype. Molecular studies revealed rearrangement of the M-bcr region and formation of BCR/ABL fusion mRNA with b3a2 configuration. Fluorescence in situ hybridization (FISH) using the abl probe showed signal on both chromosomes 9 band q34, while the bcr probe hybridized to one chromosome 22 and to one chromosome 9. In this case, as in three other cases recently described (Hagemeijer et al. and Nachava et al.), the bcr/abl rearrangement is shown to be on 9q34, instead of the usual location on 22q11.
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PMID:Reversed BCR/ABL rearrangement detected by FISH in Philadelphia negative chronic myelocytic leukemia. 762 6

We describe a patient with a t(7;11)(p15;p15) acute myeloid leukemia who was subsequently found to harbor the Philadelphia (Ph) translocation, in addition to the t(7;11), at the second relapse. A BCR/ABL transcript was detected at the second relapse by reverse transcription-polymerase chain reaction assay; the leukemic cells had a BCR/ABL fusion gene involving the minor breakpoint cluster region (minor-BCR; situated in intron 1 of the BCR gene). Although the Ph translocation is commonly detected in de novo acute leukemia and chronic myeloid leukemia as the primary leukemia-specific chromosomal translocation, our case suggests that this cytogenetic change might occur as an additional chromosomal change in neoplastic cells. Moreover, minor-BCR/ABL rearrangements may also occur as a late appearance of Ph translocation.
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PMID:Late appearance of a Philadelphia translocation with minor-BCR/ABL transcript in a t(7;11)(p15;p15) acute myeloid leukemia. 772 98

We report cases with a variant BCR/ABL mRNA expression lacking ABL exon a2 sequences. Two of these cases showed major breakpoint cluster region (BCR) exon 3 (b3) and ABL exon 3 (a3) junction (b3/a3), while the other case showed minor BCR exon 1 (e1) and a3 junction (e1/a3). One of the two cases with b3/a3 junction and the case with e1/a3 junction were diagnosed as acute lymphoblastic leukemia, and the remaining case with b3/a3 junction was chronic myeloid leukemia. Two of these cases, however, were found to have a breakpoint in the ABL gene outside of the intron between exons a2 and a3, probably 5' upstream of exon a2, suggesting that the BCR exon was spliced to ABL exon a3. These findings differ from those previously reported, in which the breakpoints in the ABL gene were between exons a2 and a3, and indicate a novel mechanism for the deletion of ABL exon a2 sequences in the formation of a variant BCR/ABL fusion transcript. The significance of the finding that a part of the SH3 region of ABL protein is missing in some Philadelphia chromosome-positive leukemias is discussed in reference to the cases reported previously.
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PMID:Heterogeneity of the breakpoint in the ABL gene in cases with BCR/ABL transcript lacking ABL exon a2. 793 65

Detection of minimal residual disease and relapse remain major problems in chronic myelogenous leukemia (CML) patients following bone marrow transplantation (BMT). In order to disclose the 9;22 Philadelphia translocation, we used a fluorescence in situ hybridization (FISH) technique. BCR and ABL gene fragments were used as probes for the detection of the BCR/ABL fusion product in peripheral blood and bone marrow cells from 11 CML patients in which 5 were post-BMT. The sensitivity and specificity of this approach were compared to conventional cytogenetic and polymerase chain reaction (PCR) methods. FISH demonstrated a high degree of sensitivity (1%) for the detection of the BCR/ABL translocation in these patients. A linear correlation was found between FISH detection of the BCR/ABL fusion product and routine chromosomal analysis (r = 0.995; p < 0.001). Detection of the BCR/ABL signal by FISH was observed in all patients showing a positive PCR signal. A significant reduction in BCR/ABL signal was observed post-transplant (p < 0.001). However, the BCR/ABL translocation was detected in four of five transplanted patients immediately (0.75-2.5 months) following transplant and was found in patients with a low expression of the translocation.
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PMID:Detection of minimal residual disease state in chronic myelogenous leukemia patients using fluorescence in situ hybridization. 807 54

Chronic myeloid leukemia (CML) is a malignant haemopoietic stem cell disorder which results in excessive production of cells of the myeloid series. It is associated with a consistent molecular abnormality, the BCR/ABL fusion gene. The product of BCR/ABL is a p210 protein tyrosine kinase but it is not known how this dictates the biological features of the disease. This review considers several key processes that can be suggested as candidate targets for the action of p210.
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PMID:Regulation of growth in chronic myeloid leukemia. 812 36

A reciprocal translocation between chromosomes 9 and 22 creates the Philadelphia (Ph1) chromosome in chronic myelogenous leukemia. This translocation results in the fusion of the ABL and the BCR genes to form a BCR/ABL fusion gene, the product of which has a greatly increased protein tyrosine kinase activity in comparison with the normal ABL protein. The chromosome 22 translocation breakpoints are concentrated within a 5.8-kilobase region named the major break-point cluster region (Mbcr). Gel mobility shift and DNase I footprinting assays have defined binding sites for three proteins, BIF 1-3 (BCR intron factors 1-3), lying within a 427-base pair fragment of the Mbcr. This 427-base pair fragment functions as a transcriptional silencer with both the BCR as well as a heterologous promoter. The silencing is position- and orientation-independent. The transcriptional effects are greatest in chronic myelogenous leukemia cells, decreased in HeLa and B-cells, and absent in T-lymphocytes. Gel mobility shift assays show a corresponding difference in pattern when the T-lymphocyte nuclear extract is compared with other cell lines. The Mbcr appears to contain a novel group of transcriptional silencers that share a common binding motif with a recently described suppressor in the mouse Adh-1 gene.
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PMID:A novel transcriptional suppressor located within a downstream intron of the BCR gene. 814 70

Decreased neutrophil alkaline phosphatase (NAP) synthesis is a classical feature of Philadelphia (Ph) positive chronic phase chronic myeloid leukemia (CML). Whether this aberration is an integral leukemic property of the cell or results from mediation by other factors is unclear. During alpha-interferon (alpha-IFN) based therapy the relationship between Ph chromosome suppression and NAP synthesis was examined. Four categories of response were observed in 19 patients studied sequentially. Significantly, persistent low NAP activity was observed in one patient in complete cytogenetic remission, while a second group of 7 patients demonstrated normal NAP activity in spite of persistence of the Ph chromosome in 100% of metaphases. In the absence of various clinical influences that can modulate NAP activity in chronic phase CML, the results reinforce the observation that the BCR/ABL fusion gene product is not a key factor influencing NAP activity in CML.
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PMID:Discordant neutrophil alkaline phosphatase activity and cytogenetic response in chronic myeloid leukemia treated with alpha-interferon. 816


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