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)

We examined bone marrow (BM) cells from 6 Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML) patients in advanced phase of the disease using conventional cytogenetic techniques and fluorescence in situ hybridization (FISH) for detection of an extra chromosome 8. All patients showed mosaicism for trisomy 8 as a secondary chromosome abnormality. For FISH, we used the D8Z5 probe specific for the centromeric region of chromosome 8 and analyzed 300 interphase nuclei and a variable number of mitoses for each patient. The percentages of metaphases carrying trisomy 8 were similar with both techniques, whereas the percentage of interphase nuclei showing three hybridization spots indicative of trisomy 8 was significantly lower than that in metaphases. This finding suggests that cells with a supernumerary chromosome 8 may have a cell cycle time shorter than that of disomic cells.
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PMID:Trisomy 8 detection in Ph+ CML patients using conventional cytogenetic and interphase fluorescence in situ hybridization techniques. 811 34

The cytosolic 185 and 210 kDa Bcr-Abl protein tyrosine kinases play important roles in the development of Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia (CML) and acute lymphoblastic leukemia (Ph+ ALL). p185 and p210 Bcr-Abl contain identical abl-encoded sequences juxtaposed to a variable number of bcr-derived amino acids. As the mitogenic and transforming activities of tyrosine kinases involve stimulation of the Ras pathway, we analyzed Bcr-Abl oncoproteins for interactions with cytoplasmic proteins that mediate Ras activation. Such polypeptides include Grb2, which comprises a single Src homology 2 (SH2) domain flanked by two SH3 domains, and the 66, 52 and 46 kDa Shc proteins which possess an SH2 domain in their carboxy-terminus. Grb2 associates with tyrosine phosphorylated proteins through its SH2 domain, and with the Ras guanine nucleotide releasing protein mSos1 through its SH3 domains. mSos1 stimulates conversion of the inactive GDP-bound form of Ras to the active GTP-bound state. In bcr-abl-transformed cells, Grb2 and mSos1 formed a physical complex with Bcr-Abl. In vitro, the Grb2 SH2 domain bound Bcr-Abl through recognition of a tyrosine phosphorylation site within the amino-terminal bcr-encoded sequence (p.Tyr177-Val-Asn-Val), that is common to both Bcr-Abl proteins. These results suggest that autophosphorylation within the Bcr element of Bcr-Abl creates a direct physical link to Grb2-mSos1, and potentially to the Ras pathway, and thereby modifies the target specificity of the Abl tyrosine kinase.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Bcr-Abl oncoproteins bind directly to activators of the Ras signalling pathway. 811 92

The karyotype of a neoplasm is known to be associated not only with the histopathologic subtype of the tumor but also with previous cytotoxic exposure and with the geographic place of origin of the patient. Some data also indicate that cytogenetic patterns vary with age and gender. To further investigate whether the frequencies of cancer chromosome aberrations differ between children and adults or between men and women, clinical and karyologic data on 14,141 neoplasms with clonal chromosome changes reported in the literature were assessed. In cytogenetically well-characterized neoplasias, recognized primary and secondary chromosome aberrations were selected, and their frequencies were calculated in men, women, children (< or = 15 years), and adults (> 15 years). In general, the frequencies of the various aberrations did not differ between men and women or between children and adults, but a few exceptions were found. In refractory anemia (RA) and RA with excess of blasts or in transformation, del(5q) was more common among women. In acute lymphoblastic leukemia (ALL-L1 + L2), t(1;19) was more frequently detected in women and del(6q) more common among men. In Philadelphia chromosome positive chronic myeloid leukemia, gain of an extra der(22)t(9;22) occurred more frequently among men. Four primary aberrations were more common in children than in adults: t(8;21) in acute myeloid leukemia (AML-M2), -7 in AML-M4, der(11q) in AML-M5, and t(8;14) in ALL-L3. On the other hand, der(16q) in AML-M4 and t(9;22) in ALL-L1 + L2 were more common in adults. The only secondary cancer chromosome aberration showing a variation with age was loss of the Y chromosome in AML-M2 with t(8;21), being more common in children than in adults. These variations might be spurious and level out when more data are collected, but more probably they reflect, for reasons presently unknown, that different genetic mechanisms may be operative in children and adults--and even in men and women--in the development of some tumors.
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PMID:Age- and gender-related heterogeneity of cancer chromosome aberrations. 822 14

Greater than 80% of patients in the stable phase of chronic myelogenous leukemia (CML) have no detectable stainable iron in the marrow yet have normal serum iron, total iron binding capacity, and serum ferritin values. We studied the pattern of marrow iron in 187 marrow aspirates from 67 patients with Philadelphia chromosome positive CML in the chronic, accelerated and blast crisis stages. Sequential marrow aspirates in 30 patients confirm that the switch from negative iron to positive iron is coincident with the development of the accelerated phase of blast crisis of CML. Our data suggest that the pattern of marrow iron staining in CML is a useful prognostic indicator of the disease evolution.
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PMID:Correlation of marrow iron patterns with disease status of chronic myelogenous leukemia. 840 Nov 82

Twenty one patients with Philadelphia chromosome positive CML were treated with natural interferon alpha. All patients were in the chronic phase, 5 were untreated and 16 had been previously treated with busulfan or hydroxyurea. Eight patients in complete remission (CR) were given IFN subcutaneously at a dose of 5 x 10(6) unit per day as maintenance therapy, whereas 13 non-CR patients were given 2. 5 approximately 10 x 10(6) units for remission induction. Doses and intervals of IFN were adjusted to maintain the WBC count below 5 x 10(9)/l, but additional drugs were given when the WBC count could not be controlled with IFN alone. Six out of 10 evaluable non-CR patients attained CR with IFN only and 4 others achieved with additional drug. Cytogenetic responses were evaluated in 15 patients. CCR, PCR and MCR were attained in 5, 2 and 1 patients respectively. Southern blotting method showed that the BCR gene rearrangement disappeared in 5 out of 13 patients. Cytogenetic response rate was not different between untreated and previously treated patients, however it differed between patients with or without additional drug. The time to first cytogenetic effect was within 12 months in almost all effective cases. Fever and general fatigue were seen in almost all patients. IFN administration was discontinued only patients with severe skin eruption (3 patients) and bone marrow aplasia (1 patient).
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PMID:[Natural interferon alpha for chronic myelogenous leukemia in the chronic phase: hematologic, cytogenetic and molecular response]. 853 23

Antisense oligonucleotides were used to determine the role of the BCR-ABL gene in the proliferation of chronic myeloid leukaemia (CML) clonogenic cells. Peripheral blood Philadelphia chromosome positive cells were obtained from eight CML patients at diagnosis (chronic phase = 7; accelerated phase = 1). Mononuclear cells were incubated with synthetic antisense 18-mer oligonucleotides complementary to the two different junctions b2a2 or b3a2. The type of junction (b2a2 or b3a2) was previously determined by RT-PCR techniques. Cells incubated for 12 to 14 hours with or without sense oligonucleotides served as controls. After incubation with oligonucleotides, the cell DNA synthesis was analysed by flow cytometry using the BrdUrd/DNA method and the cell plating efficiency in methylcellulose was determined. In six of the seven patients in chronic phase, there was a significant inhibition of CFU-GM production which was only 68.4 +/- 19%; (p < .01) of that found in controls. The S phase index, which depends upon the percentage of S phase cells as well as the fluorescence intensity, was 48 +/- 29% (p < .01) of the control values for the seven patients in chronic phase. Interestingly, for the only CML patient in accelerated phase, antisense oligomers had no inhibitory effect on either the production of CFU-GM or the number of S phase cells. In improving the specificity of oligomers, it might be useful for gene-targeted anti-leukemic therapy and/or bone marrow purging.
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PMID:Specific antisense oligomer anti Bcr-abl junctions in chronic myeloid leukemia: a cell cycle analysis and CFU-GM study. 859 Aug 42

Interferon-alpha (IFN-alpha) induces cytogenetic responses of variable degree in patients with chronic myelogenous leukemia (CML). We sought to establish the relationship between BCR-ABL transcript numbers measured by competitive 2-step reverse transcription polymerase chain reaction (RT-PCR) and cytogenetic status in CML patients treated with IFN-alpha. A total of 250 peripheral blood and 55 bone marrow samples with 127 Philadelphia chromosome positive (Ph+) and 6 Ph-/BCR-ABL+ CML patients were investigated. Twenty-one patients were studied at diagnosis with IFN-alpha, 24 had a complete cytogenetic response, 21 a partial response, 12 a minor response, 26 no response, and 23 were unknown. Using nested RT-PCR, all 305 samples were positive for BCR-ABL transcripts. To standardize results for variability in RNA and cDNA quantity and quality, we quantified total ABL transcripts in each sample as internal control. The validity of ABL as internal control was shown by comparison with glucose-6-phosphate dehydrogenase transcript levels in 145 samples. The median BCR-ABL transcript numbers (and BCR-ABL/ABL ratios expressed as percentages) were 400/micrograms RNA (O.04%) in complete responders, 20,500/micrograms RNA (7.1%) in partial responders, 170,000/micrograms RNA (21.0%) in minor responders, and 430,000/micrograms RNA (58.7%) in nonresponders (P < .001). The cytogenetic results correlated with the BCR-ABL transcript numbers (r = .82; P < .001) and BCR-ABL/ABL ratios (r = .84; P < .001). Grouping the ratios BCR-ABL/ABL as less than 2%, 2% to 14% and greater than 14% to compare with cytogenetic complete response, partial response, and minor/nonresponse, the concordance between the two methods was 82% (chi2 P< .0001). We conclude that quantitative PCR with internal controls is as sensitive and reliable method for monitoring patients on IFN-alpha and reduces the need for repeated marrow investigations.
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PMID:Quantification of residual disease in chronic myelogenous leukemia patients on interferon-alpha therapy by competitive polymerase chain reaction. 860 46

Recent advances in molecular biological techniques have contributed to the tremendous progression made in the field of diagnosis of leukemia. Discovery of T- or B-lymphocyte associated genes, tumor specific genes and genes involved in chromosomal translocation has made it possible to detect leukemia cells by Southern blotting, PCR, RT-PCR or fluorescence in situ hybridization (FISH). The recently developed FISH is a simple, rapid and accurate method and requires a very small amount of specimen (about 500-1000 cells). It is possible to obtain results within 48 hours of sampling. This lecture were focused on two topics; 1) The application of FISH method in the diagnosis of leukemia using three types of probes (whole chromosome painting probe, centromeric probes and oncogene specific probes) and their combinations. 2) Clarification of concepts made by molecular biology especially in Philadelphia chromosome positive leukemia, Ph-negative chronic myelocytic leukemia, endemic/sporadic type of Burkitt's lymphoma, biphenotypic leukemia and leukemia with specific translocations.
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PMID:[Progress in diagnosis of leukemia]. 881 59

In chronic myeloid leukaemia (CML), disease progression from the initial chronic phase to the acute phase or blast crisis has previously been shown to be correlated with progressive increases in hyper-methylation of the calcitonin gene, located at chromosome 11p15. However, sequential studies of individual patients were not performed in these investigations. We have analysed 44 samples from nine patients with typical Philadelphia chromosome positive CML throughout their disease progression to determine the methylation state of the calcitonin gene at these time points. Densitometry was used to quantitate the ratio of the normal 2.0 kb Hpa II fragments, indicating normal methylation status of the gene, compared to the intensity of the abnormal, hyper-methylated, 2.6-3.1 kb Hpa II fragments. We found a gradual increase in the ratio of methylated:unmethylated calcitonin gene during chronic phase with a dramatic rise at blast crisis. Further, the ratio of the abnormal hypermethylated 3.1 kb fragments to the methylated 2.6 kb fragment resulted in the identification of a clonal expansion of abnormally methylated cells. This expansion of cells with hypermethylation of the calcitonin gene during chronic phase was shown to coincide with the presence of a mutation in the p53 gene. The data presented in this study would suggest that an increased methylation status of the calcitonin gene during disease progression may indicate the expansion of abnormal blast cell populations and subsequent progression to blast crisis.
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PMID:Increasing methylation of the calcitonin gene during disease progression in sequential samples from CML patients. 894 87

According to strict morphological, biochemical and cytogenetic criteria Philadelphia chromosome positive essential thrombocythemia and chronic granulocytic leukemia constitute a separate malignant and individual disease entity, whereas Philadelphia chromosome negative essential thrombocythemia, polycythemia vera and agnogenic or megakaryocytic myeloid metaplasia form a chronic proliferation of three hematopoietic cell lines. Histopathology from bone marrow biopsies permits the characterization and diagnostic differention of the various myeloproliferative disorders and appears to be a main and specific diagostic criterion for polycythemia vera and essential thrombocythemia. Hemorrhagic thrombocythemia is a clinical syndrome of recurrent spontaneous mucocutaneous and secondary hemorrhages often preceded by thromboses, extremely high platelet counts, pseudohyperkalemia, increased bone marrow cellularity and frequently splenomegaly. The diagnostic criteria of essential thrombocythemia with paradoxical occurrence of thrombotic events and hemorrhagic manifestations are a platelet count in excess of 1000 x 10(9)/L and increased bone marrow cellularity in the majority of the cases. Erythromelalgia and other microcirculatory ischemic or thrombotic events or accidents in essential thrombocythemia and polycythemia vera already occur at platelet counts in excess of the upper limit of normal. First line treatment options in essential thrombocythemia and polycythemia vera are control of platelet function with low-dose aspirin and reductive control of platelet count and erythrocytes by bloodletting, interferon and busulfan or hydroxyurea monochemotherapy.
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PMID:The myeloproliferative disorders. An historical appraisal and personal experiences. 895 68


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