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)

The Philadelphia chromosome (Ph') is found in the blood cells of about 90% of patients with chronic myeloid leukaemia (CML) and usually results from the reciprocal chromosome translocation t(9;22). This translocation relocates the proto-oncogene c-abl, normally found on chromosome 9q34, to within the breakpoint cluster region (bcr) on chromosome 22q11 (refs 3-8). The juxtaposition of c-abl and the 5' portion of bcr appears to be the critical genomic event in CML and results in a novel 8-kilobase (kb) fused abl/bcr transcript and a c-abl-related protein of relative molecular mass 210,000 (ref.11). About 10% of adult patients diagnosed as CML lack the Ph' chromosome; they represent a heterogeneous group of disorders which are difficult to diagnose precisely. We have examined five patients with CML whose leukaemic cells have a normal karyotype. We report here that two of the patients showed the same genomic change as occurs in Ph'-positive CML, but the change resulted from a mechanism other than chromosomal translocation. The remaining three patients showed no genomic rearrangement. This genomic diversity correlated with the clinical differences between the patients.
 ...
PMID:Genomic diversity correlates with clinical variation in Ph'-negative chronic myeloid leukaemia. 300 92

The consistent cytogenetic translocation of chronic myelogenous leukemia (the Philadelphia chromosome, Ph1) has been observed in cells of multiple hematopoietic lineages. This translocation creates a chimeric gene composed of breakpoint-cluster-region (bcr) sequences from chromosome 22 fused to a portion of the abl oncogene on chromosome 9. The resulting gene product (P210c-abl) resembles the transforming protein of the Abelson murine leukemia virus in its structure and tyrosine kinase activity. P210c-abl is expressed in Ph1-positive cell lines of myeloid lineage and in clinical specimens with myeloid predominance. We show here that Epstein-Barr virus-transformed B-lymphocyte lines that retain Ph1 can express P210c-abl. The level of expression in these B-cell lines is generally lower and more variable than that observed for myeloid lines. Protein expression is not related to amplification of the abl gene but to variation in the level of bcr-abl mRNA produced from a single Ph1 template.
 ...
PMID:Variable expression of the translocated c-abl oncogene in Philadelphia-chromosome-positive B-lymphoid cell lines from chronic myelogenous leukemia patients. 301 46

The primary structure of normal abl protein was determined by sequencing the coding region of its cDNA. abl contains two alternative 5' exons spliced to a common set of 3' exons to yield the two major abl RNA transcripts. These transcripts initiate in different promoter regions and give rise to proteins that vary in their N-termini. In the human cell line K562, abl is translocated from chromosome 9 to within the bcr gene on chromosome 22. Within the fused bcr-abl gene, abl exon II alternatively splices to two adjacent bcr exons. This phenomenon is seen in many patients with chronic myeloid leukemia.
 ...
PMID:Alternative splicing of RNAs transcribed from the human abl gene and from the bcr-abl fused gene. 302 37

The major consequence of the formation of the Philadelphia (Ph1) chromosome characteristic of leukemia cells of patients with chronic myelogenous leukemia (CML) is fusion of c-abl and bcr genes. Using a sensitive RNase protection technique, we analyzed mRNA from a large number of CML patients. In most, we identified one or both species of bcr-abl chimeric transcripts. These two mRNAs vary in the specific bcr exon joined to abl exon II and are translated into slightly different proteins. The amounts of the fused mRNA within leukemia cells vary considerably between individuals and do not correlate with the phase of the disease.
 ...
PMID:bcr-abl RNA in patients with chronic myelogenous leukemia. 310 69

The reciprocal translocation between human chromosomes 9 and 22, termed the Philadelphia chromosome (Ph1), is observed in more than 90% of patients with chronic myelogenous leukemia. This translocation fuses sequences from a variable distance 5' to the c-abl locus on chromosome 9 to sequences in a breakpoint cluster region (bcr) on chromosome 22. The appearance of the Ph1 chromosome is correlated with the production of a novel 8.7-kb RNA transcript containing both bcr and c-abl sequences as well as with a 210-kd phosphoprotein (p210c-abl) representing non-abl polypeptide sequences fused to c-abl-derived sequences. Antibodies prepared to a number of different c-abl domains and to bcr determinants were employed to characterize the normal and altered c-abl gene products. By combining a variety of cDNA cloning techniques, we have isolated bcr/abl clones representing 8.7 kb of contiguous mRNA sequence.
 ...
PMID:Molecular cloning and serological characterization of an altered c-abl gene product produced in Ph1 CML patients. 312 80

Leukemic cells from patients with Philadelphia chromosome (Ph1)-positive chronic myelogenous leukemia (CML) contain a 210 kDa protein (P210bcr-abl) with a protein tyrosine kinase activity that is a product of fused bcr and abl genes. We have prepared two monoclonal anti-peptide antibodies, one from each gene product, and have affinity purified each. Incubation of anti-abl (c-abl 51-64) immunoprecipitates of K562 cells with [gamma-32P]ATP in protein kinase assays resulted in the labeling of P210bcr-abl and a 53 kDa (ph-P53) protein. Increasing concentrations of antibody detected similar ratios of P210bcr-abl: ph-P53, suggesting the presence of a complex between the proteins. Several different anti-abl and anti-bcr antibodies detected the ph-P53/P210 complex. Sodium dodecyl sulfate (SDS) treatment without 2-mercaptoethanol eluted P210bcr-abl and ph-P53 from the monoclonal antibody in the form of complexes which migrated on 6% SDS-polyacrylamide gels and had apparent molecular weights of 275,000 and more than 500,000. Both complexes yielded ph-P53 and P210bcr-abl upon treatment with SDS-mercaptoethanol. Studies involving glycerol gradient centrifugation also detected complexes of P210bcr-abl and ph-P53. Our results indicate that ph-P53 is not a degraded product of P210bcr-abl, does not share antigenic determinants with P210bcr-abl since it is not recognized by anti-abl and bcr antibodies in immunoblots, is not the phosphorylated heavy chain of immunoglobulin G, and is different from p53 (the nonviral T protein) complexed to the large T antigen of simian virus 40. Previous studies (Maxwell et al., 1987) have shown that ph-P53 has a different peptide map than P210bcr-abl. Therefore, we conclude that ph-P53 is a distinct cellular protein complexed to P210bcr-abl in K562 cells.
 ...
PMID:A novel 53 kDa protein complexed with P210bcr-abl in human chronic myelogenous leukemia cells. 313 27

In chronic myeloid leukemia (CML), a chromosome translocation has fused the bcr gene to the c-abl oncogene, such that a chimeric bcr-abl polypeptide can be made. To explore the biological properties of bcr-abl and compare them with those of the Abelson virus (AMuLV) transforming gene (gag-v-abl), we have used either a synthetic bcr-v-abl gene that mimics the translocation product or, in some experiments, a bcr-c-abl cDNA. A new retroviral vector was used to introduce the genes into the factor-dependent myeloid line FDC-P1. Both bcr-abl and v-abl efficiently rendered the myeloid cells factor independent and tumorigenic. Their fully autonomous growth may be due to the myeloid growth factor interleukin-3 (IL-3) made in small amounts by the infected cells. Hence autocrine factor production may feature in CML development and Abelson virus transformation.
 ...
PMID:bcr-abl oncogene renders myeloid cell line factor independent: potential autocrine mechanism in chronic myeloid leukemia. 314 34

The purpose of this study was to determine the feasibility of using the technique of premature chromosome condensation to detect the in vivo maturation of abnormal elements in patients with chronic myelogenous leukemia (CML), myelodysplastic syndrome, and acute leukemia. Patients were chosen for study if there were a clinical suggestion of in vivo maturation and a leukemic clone exhibiting a distinguishable karyotypic abnormality. Mature peripheral blood granulocytes were enriched by two-step Ficoll-Hypaque gradient sedimentation and fused with mitotic Chinese hamster ovary cells to induce the formation of prematurely condensed chromosomes (PCC). These PCC were then analyzed for chromosome number per cell (in the case of patients with a numerical abnormality) or by G-banding (in the case of specific translocations). Of 13 patients chosen for study, 12 showed karyotypic evidence for maturation of the abnormal elements in vivo. Maturation was observed in a number of clinical situations including before treatment in benign CML and myelodysplasia, after low-dose and high-dose chemotherapy in myelodysplasia and acute myelogenous leukemia (AML), and in remission. These results suggest that the technique of premature chromosome condensation can be a powerful tool in better understanding the biology of disease and mode of response to therapy in vivo in patients with leukemia and preleukemic syndromes, especially during treatment with agents thought to induce maturation of the leukemic elements.
 ...
PMID:Detection of leukemic clone maturation in vivo by premature chromosome condensation. 319 73

A DNA region on chromosome 22, designated M-BCR, contains the chromosomal breakpoint of the Philadelphia (Ph) translocation in all Ph positive CML patients studied to date. M-BCR is part of a gene, BCR, oriented with its 5' end towards the centromere of chromosome 22. All of the CML DNAs analysed have a breakpoint within introns of the BCR gene. As a consequence of the Ph translocation the 3' end of the BCR gene has been translocated to chromosome 9, while the 5' part remains on the Ph chromosome. The remaining BCR sequences act as an acceptor for a chromosome 9 gene, the ABL oncogene: the ABL oncogene is fused in a head-to-tail fashion to the chromosome 22 sequences. This genomic configuration results in the transcription of a novel chimeric mRNA consisting of 5' BCR sequences and 3' ABL oncogene sequences. In K562, a cell line derived from a CML patient, and in five CML patients such chimeric BCR/ABL transcripts have been demonstrated. An abnormally sized ABL protein has been detected in the cell line K562 and in leukaemic cells from patients. This protein represents the translational product of the chimeric mRNA. The role of the BCR part of the fusion protein is unknown; it is possible that the BCR moiety could alter the structure of the ABL protein and unmask its tyrosine kinase activity. By analogy with the gag/v-abl polyprotein, the CML-specific BCR/ABL protein might have transforming activity and could play an essential role in the generation and/or maintenance of CML.
 ...
PMID:The BCR/ABL hybrid gene. 333 59

Peripheral blood mononuclear cells from a patient with acute myeloid leukemia (AML) and spleen cells from a patient with chronic myeloid leukemia (CML) were fused with HAT-sensitive human B lymphoma cells (RH-L4) in attempts to generate human monoclonal antibodies (Mab) against antigens with high specificity for myeloid leukemia cells. Forty-seven of 246 hybridomas secreted Ig that bound to AML cell surface constituents, as determined by FACS analysis of viable cells that were FITC-stained with the human Mab as the first-step reagent and FITC-conjugated rabbit anti-human Ig as second-step. Two of the 47 human Mab (one from each patient and designated AML-19 and CML-20, respectively) bound to both autologous and allogeneic myeloid leukemia cells. No significant binding was observed to cell surface constituents on human bone marrow cells, granulocytes, lymphocytes, erythrocytes, thymocytes, monocytes, lymphoblastic leukemia cells, fibroblasts, malignant B and T lymphocytic cell lines, and murine bone marrow cells. Both human Mab were IgG and were cytotoxic to myeloid leukemia cells in the presence of complement. About 70% of peripheral blood cell samples from 46 AML patients contained AML-19- and CML-20-positive cells, but the reactivity pattern had no correlation to the morphologic FAB classification of the samples. The promyelocytic HL60 cell line and the K562 cell line reacted with the two antibodies. Dot blot analysis of binding of AML-19 and CML-20 to cellular extracts immobilized on nitrocellulose paper showed that both human Mab in this assay also reacted with normal bone marrow cells. This was supported by microscopic immunofluorescence because both human Mab stained intracytoplasmatic structures in normal bone marrow cells, but both intracytoplasmatic and cell surface components stained in myeloid leukemia cells. Moreover, immunoblotting demonstrated that both human Mab in leukemia cells reacted with two cellular proteins with Mr approximately 14,500 and 18,000, and in normal bone marrow cells with a molecule with Mr approximately 20,000. Immunoprecipitation of cell membrane molecules with both the AML-19 and CML-20 antibody precipitated from leukemic cells only the molecule with Mr approximately 18,000 and no components from normal bone marrow cells. It is concluded that myeloid leukemogenesis may result in generation of cell surface expression of either new or abnormally processed molecules that are immunogenic in the autochthonous host. These molecules may also be useful as markers in diagnosis of myeloid leukemia.
 ...
PMID:Antibody-producing human-human hybridomas. III. Derivation and characterization of two antibodies with specificity for human myeloid cells. 345 56


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>