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)

Molecular events associated with the transformation into blast crisis phase in Ph1-positive CML were analyzed in the present study. The 9;22 chromosomal translocation in CML generates the bcr/abl fused gene coding P210bcr/abl that has enhanced tyrosine kinase activity. In 55 CML cases, Southern and RT-PCR analysis revealed that breakpoints of the bcr gene on chromosome 22q11 were clustered in M-bcr, except for one case and no obvious difference was observed between chronic and crisis phases. However, blast crisis cells displayed enhanced the expression of bcr/abl mRNA, when compared with those in chronic phase cells. By DNA transfection and PCR analysis, the point-mutational activation of N-ras oncogene was rarely identified, and no point-mutational activation of fms gene was found in the crisis phase cases. On the other hand, 2 out of 13 crisis cases contained gross alteration of p53 anti-oncogene. Furthermore, all 4 myeloid crisis cases and K562 cells showed disappearance of the P53 transcript, and MC3 cells derived from a myeloid crisis case showed an aberrant transcript, whereas chronic phase cases, Ph1-positive ALL cell lines and lymphoid crisis cases including NALM-1 cells showed normal expression of the P53 gene. At present, the precise mechanism associated with the blastic trans-formation in CML remain to be determined. The present study suggested one possibility that a selective and progressive process of Ph1 clone with high expression of the bcr/abl gene may be involved with the transformation into non-lymphoid crisis phases from chronic phases. In addition, this progression may be accelerated by the alteration of p53 anti-oncogene, or/and rarely by the point-mutational activation of ras oncogene family.
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PMID:[Molecular analysis of transformation into blast crisis in chronic myelogenous leukemia]. 850 66

The 22nd chromosome is known mainly due to chromosome (Philadelphia) which is its derivative-a typical cytogenetic sign of chronic myeloid leukaemia (CML). The molecular genetic finding in these patients is the fused gene which developed by combination of the 3' part of the oncogene ABL from chromosome 9 and 5' part of the gene which developed by combination of the 3' part of the oncogene ABL from chromosome 9 and 5' part of the BCR "gene". The product of the gene retains the original kinase activity (ABL) which is even higher. Detection of BCR/ABL is an important diagnostic aid whic makes it possible to investigate residual diseases in patients after intensive treatment and transplantation of bone marrow and early detection of possible relapses. Among locuses of the 22nd chromosome the author mentions also the locus of the second one of the light immunoglobulin chains-lambda, incl. some of its "related" genes, the group of crystalline locuses (CRYB), the locus of the beta-chain of the GM-CSF receptor, the myoglobin locus (MB) and finally locus NF2 of central neurofibromatosis-bilateral neurinoma of the acoustic nerve.
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PMID:[The human genome--chromosome 22]. 859 11

In Philadelphia chromosome (Ph1) positive leukemias, the BCR gene is fused to the ABL gene. The resulting chimeric BCR-ABL oncoproteins are thought to play a central role in the pathogenesis of these diseases. We previously described two exons that can be spliced alternatively to the second BCR exon in place of the first exon to form minor messages. In this paper, we localize the alternative exons to a 4.1 kb BglII fragment in the 5' region of the large first intron of the BCR gene. This genomic structure is of interest because of its analogy to the organization of the ABL gene and because this part of the gene is not affected by the breakpoints occurring in Ph1-positive acute lymphoblastic leukemia (ALL). Using the reverse transcriptase-polymerase chain reaction (RT-PCR), we detected the alternative messages in all cases of chronic myelogenous leukemia (CML) tested, including seven samples in the chronic phase, five in the accelerated phase and nine in the acute phase, as well as in the majority of other samples studied. These findings suggest a functional role for the variant transcripts.
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PMID:The first intron of the BCR gene contains two minor alternative exons. 863 66

The Philadelphia chromosome (Ph) is found in both chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL). The Ph translocation, t(9;22)(q34;q11), can disrupt the BCR gene on chromosome 22 in one to two areas called the major (Mbcr1) and minor (mbcr1) breakpoint cluster regions. In CML the breakpoint has been mapped almost exclusively to Mbcr1, whereas in Ph positive ALL both Mbcr1 and the upstream mbcr1 breakpoints have been described. In this communication we describe an unusual patient with typical chronic phase Ph positive CML and evidence of the uncharacteristic mbcr1 breakpoint, predicting expression of the ALL-type p190 fusion protein. Fluorescence in situ hybridization demonstrated BCR gene rearrangement, the reverse transcription polymerase chain reaction detected the BCR-ABL fusion mRNA characteristic of the mbcr1 breakpoint, and failed to detect BCR-ABL mRNA characteristic of the Mbcr1 breakpoint. Southern blot analysis revealed no rearrangement in Mbcr1, and direct sequencing of the PCR product confirmed it to be the ALL-type mbcr1 fusion mRNA with the first exon of the BCR gene fused to ABL exon a2. This case differs from the previously reported cases of "p190" CML in that the patient presented without abnormal hematopoietic features other than those found in typical CML and provides further evidence that the p190 mRNA is not sufficient to cause an acute rather than chronic leukemia.
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PMID:Unusual expression of mRNA typical of Philadelphia positive acute lymphoblastic leukemia detected in chronic myeloid leukemia. 875 76

The hypothesis that minor bcr/abl fusion mRNA is produced in blast crisis of chronic myelogenous leukemia (CML) is examined. The RNA transcripts encoding the minor and major bcr/abl fused protein were detected by polymerase chain reaction (PCR) using RNA from peripheral blood or bone marrow cells of eight patients with blast crisis or accelerated phase of CML. The mRNA encoding for major bcr/abl was detected in all eight cases. In four patients, however, transcripts encoding for minor bcr/abl mRNA were detected, as well as major bcr/abl mRNA. The presence of minor bcr/abl mRNA was verified with the hybridization with a junction-specific probe and DNA sequencing analysis of PCR products. The appearance of minor bcr/abl fusion mRNA was associated with the lymphoblastic immunophenotype of the blast cells. In two of these four patients, samples of initial diagnosis of chronic phase of CML were available, which did not show minor bcr/abl transcript. We conclude that the appearance of minor bcr/abl mRNA transcript is associated with the terminal evolution of CML in lymphoblastic crisis.
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PMID:The dual expression of minor and major bcr/abl chimeric mRNA in blast crisis of chronic myelogenous leukemia. 879 91

The Philadelphia chromosome (Ph) is found in most chronic myelogenous leukemia (CML) patients. The bcr-abl oncoprotein (P210 or P185), the product of the fused bcr-abl gene produced by the Ph, is known to be the major factor in initiation and maintenance of the leukemic state in these types of leukemias. The authors have devised a Western blot test to detect and quantitate the bcr-abl oncoprotein in blood and bone marrow cells. The authors analyzed 1,155 peripheral blood samples from CML patients, for which there were same day Ph data, to determine if there was a correlation between bcr-abl protein levels and the percentage of Ph. A ratio of bcr-abl protein (P210 or P185) to normal abl protein (P145), the latter is ubiquitously expressed in all blood cells, has been established as a criterion for quantitating bcr-abl levels. The bcr-abl/abl protein ratio from 399 patient who were 100% Ph-positive had a mean of 2.47 (standard error [SE] of +/- 0.05); no false negatives were detected. A decreasing ratio was found in patients with decreasing percentages of Ph. The relationship between the ratio of bcr-abl/abl proteins to the percentage of Ph-positive cells was nearly linear in 392 patients with Ph percentages between 5% to 95% (r = 0.97, P < .001). For patients in remission with no detectable Ph, the bcr-abl/abl ratio had a mean of 0.01 (SE = 0 +/- 0.00). The level of bcr-abl expression in samples from peripheral blood and bone marrow also were compared. The results indicated that the amount of bcr-abl protein within peripheral blood is usually similar to that in marrow. In conclusion, quantitation of the bcr-abl oncoprotein in peripheral blood cells or marrow cells as measured by a Western blot assay provides reliable data for both diagnosis and monitoring patients with pH-chromosome positive leukemia.
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PMID:Comparison of bcr-abl protein expression and Philadelphia chromosome analyses in chronic myelogenous leukemia patients. 885 30

DR-nm23 cDNA was cloned recently by differential screening of a cDNA library derived from chronic myelogenous leukemia-blast crisis primary cells. It is highly homologous to the putative metastasis suppressor nm23-H1 gene and the closely related nm23-H2 gene. When overexpressed in the myeloid precursor 32Dcl3 cell line, it inhibited granulocyte colony-stimulating factor-stimulated granulocytic differentiation and induced apoptosis. We have now found that the expression of DR-nm23 is not restricted to hematopoietic cells but is also detected in an array of solid tumor cell lines, including carcinoma of the breast, colon, and prostate, as well as the glioblastoma cell line T98G. We have also isolated both the gene and its 5'-flanking region and found that DR-nm23 localizes on chromosome 16q13. The gene consists of six exons and five introns. When fused in-frame to the nucleotide sequence for the green fluorescent protein and transfected in SAOS-2 cells, it generates a protein of the predicted size that localizes to the cytoplasm. The 5'-flanking region of DR-nm23 does not contain a canonical TATA box or a CAAT box, but it is G+C rich and contains two binding sites for the developmentally regulated transcription factor activator protein 2 (AP-2). Transient expression assays of DR-nm23 promoter-chloramphenicol acetyltransferase constructs demonstrated that the segment from nucleotides -1028 to +123 has the highest activity in hematopoietic K562 cells and in TK-ts13 hamster fibroblasts. Moreover, AP-2 induced a 3-fold transactivation of the DR-nm23 5'-flanking segment from nucleotides -1676 to +123 and interacted specifically with oligomers containing putative AP-2 binding sites (-936 to -909, and -548 to -519) as indicated by electrophoretic mobility shift assay. Furthermore, nuclear run-on assays from high and low DR-nm23-expressing cells (K562 and CCRF-CEM, respectively) revealed similar transcription rates. Therefore, the regulation of the DR-nm23 gene expression might involve other mechanisms occurring at posttranscriptional and/or translational levels.
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PMID:Gene structure, promoter activity, and chromosomal location of the DR-nm23 gene, a related member of the nm23 gene family. 906 90

The t(3;21)(q26;q22), which is usually found in blastic crisis of chronic myelocytic leukemia or myelodysplastic syndrome-derived leukemia, produces an AML1/EVI-1 fusion protein of 180 kD containing amino-terminal half of AML1 including a runt homology domain which is fused to the entire of zinc finger EVI-1 protein. Thus, AML1/EVI-1 fusion protein is a chimeric transcription factor including a runt homology domain from AML1 and two zinc finger domains from EVI-1, totally three DNA binding domains, and an acidic domain from EVI-1. The AML1/EVI-1 fusion protein possesses the dual functions, namely, differentiation block and stimulation of proliferation. The ability of differentiation block depends on the runt homology domain in the AML1 part and the effect to stimulate proliferation depends on the second zinc finger domain in the EVI-1 portion. The AML1/EVI-1 could play an important role in leukemic progression of chronic myelocytic leukemia by these dual functions as a transcription factor.
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PMID:Molecular mechanism of blastic crisis in chronic myelocytic leukemia. 920 39

With the eventual goal of developing a treatment for chronic myelogenous leukemia (CML), attempts have been made to design hammerhead ribozymes that can specifically cleave BCR-ABL fusion mRNA. In the case of L6 BCR-ABL fusion mRNA (b2a2 type; BCR exon 2 is fused to ABL exon 2), which has no effective cleavage sites for conventional hammerhead ribozymes near the BCR-ABL junction, it has proved very difficult to cleave the chimeric mRNA specifically. Several hammerhead ribozymes with relatively long junction-recognition sequences have poor substrate-specificity. Therefore, we explored the possibility of using newly selected DNA enzymes that can cleave RNA molecules with high activity to cleave L6 BCR-ABL fusion (b2a2) mRNA. In contrast to the results with the conventional ribozymes, the newly designed DNA enzymes, having higher flexibility for selection of cleavage sites, were able to cleave this chimeric RNA molecule specifically at sites close to the junction. Cleavage occurred only within the abnormal BCR-ABL mRNA, without any cleavage of the normal ABL or BCR mRNA. Thus, these chemically synthesized DNA enzymes seem to be potentially useful for application in vivo , especially for the treatment of CML, if we can develop exogenous delivery strategies.
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PMID:Comparison of the specificities and catalytic activities of hammerhead ribozymes and DNA enzymes with respect to the cleavage of BCR-ABL chimeric L6 (b2a2) mRNA. 922 7

In chronic myelogenous leukemia (CML), abnormalities develop in hematopoietic stem cells, affecting three hematopoietic cell series, including leukocytes, erythrocytes, and platelets. The occurrence of the Philadelphia (Ph1) chromosome and BCR/ABL fused genes are involved in its pathophysiology. Methods of treating CML consist of bone marrow transplantation, and administration of interferon (IFN) and other antineoplastic drugs. Bone marrow transplantation is strongly recommended when the patient is young (usually aged 45 years or younger) and a donor with identical human leukocyte antigens (HLA) is available. When bone marrow transplantation is impossible, administration of IFN is the treatment of choice. IFN administration may induce disappearance or a decrease in the Ph1 chromosome. IFN administration has been demonstrated to significantly increase the survival rate over conventional chemotherapy (hydroxyurea or busulfan).
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PMID:[Recent progress in therapy for chronic myelogenous leukemia]. 923 58


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