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)

Chronic myelogenous leukemia presents two distinct clinical phases: the chronic phase is characterised by a marked expansion of the myeloid compartment which still retains a normal differentiative capacity, whereas a differentiation block is the clinical hallmark of the acute transformation. The molecular mechanism underlying the CML progression are still poorly understood. The occurrence of additional molecular lesions, involving the p53, the RAS and the p16 genes may complement and fulfil the BCR/ABL transforming potential, finally leading to an acute leukemic phenotype. However, several lines of evidence suggest that also quantitative changes of the BCR/ABL transcript amounts could explain the progression of the leukemic phenotype in the BCR/ABL-positive hematologic malignancies.
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PMID:Molecular events in chronic myeloid leukemia progression. 920 43

The molecular mechanisms responsible for progression of chronic myelogenous leukemia (CML) to blast crisis have not been well defined. Blast crisis may be partially related to inactivation of tumor suppressor genes/such as p53 or retinoblastoma (Rb) gene. There is evidence for an association of blast cell phenotypes in CML with alterations of these genes: a strong association of myeloid phenotypes with abnormalities of the p53 gene and a weaker association of lymphoid phenotypes with abnormalities of the Rb system. We found a marked decrease in Rb gene product and rearrangements of the p53 gene simultaneously in two cases of biphenotypic blast crisis of CML (myeloid and B-lymphoid). These results support the association of blast cell phenotypes with alterations in tumor suppressor genes in CML blast crisis.
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PMID:Biphenotypic blast crisis of chronic myelogenous leukemia: abnormalities of p53 and retinoblastoma genes. 925 Aug 29

Mutations of the p53 tumor suppressor are often observed in various human tumors, including blast crisis of chronic myelogenous leukemia (CML). The pattern of p53 mutations in CML shows some peculiarities compared with majority of other malignancies. In particular, the substitutions at codon 273, one of the most common p53 alterations in various tumors, are not characteristic of CML. To test whether the distinctions in the pattern of p53 mutations are connected with some peculiarities of the biological effects of different mutant proteins in leukemic cells, we obtained and analyzed a panel of human K562 cell sublines expressing various exogenous p53; human Pro156, His175, His194, Trp248, and His273, or murine temperature-sensitive (ts) Val135 that has properties of mutant protein at 37 degrees C, but shows activities of the wild-type (wt) p53 at 32 degrees C. We have found that expression of wt-p53 enhanced the dependence of cells on growth/survival factors. Incubation of sparse (< 10(5) cells per/ml) K562/Val135 cultures at 32 degrees C caused apoptosis. In media conditioned by cells of different origin (K562, colorectal carcinoma LIM1215, Rat1 fibroblasts) the p53-dependent apoptosis was inhibited. Under such conditions the expression of ts-wt-p53 was accompanied by dramatic increase in the number of cells producing specific markers of erythroid differentiation-GlycPhA and Ag-Eb. Unlike to the wt-p53, the majority of tumor-derived mutant p53 (Pro156, His175, His194) increased cell survival in low serum and decreased the number of cells expressing Glyc-PhA, CD9, CD15, and CD71 differentiation antigens. On the other hand, expression of His273-p53 caused significant augmentation in the number of CD9-positive cells and enhanced the dependence on growth/survival factors that are present in serum or conditioned media. The data obtained allow to suggest that an unusual pattern of p53 mutations in CML reflects some peculiarities of biological effects of certain mutant proteins on differentiation and viability of leukemic cells.
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PMID:Distinct effects of various p53 mutants on differentiation and viability of human K562 leukemia cells. 926 86

A longitudinal investigation using fluorescence in situ hybridization (FISH) analysis, PCR-SSCP, and in situ detection of apoptosis by the terminal deoxynucleotidyl Transferase (TdT) method was carried out on 13 chronic myelogenous leukemia (CML) patients to study the p53 gene behavior and the apoptotic process during the course of the disease. At diagnosis, FISH showed no loss of the p53 gene on interphase nuclei, and no point mutation was detected by polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) and sequencing. During the disease course, FISH analysis showed a significative loss of allele (LOA) rate for the p53 gene in eight patients that in seven cases was associated with a suppression of apoptotic process and the progressive expansion of the p53+/p53- clone. DNA sequencing showed in two of these eight patients a point mutation on the other allele, consisting in the formation of a stop codon in one case, and in a frameshift mutation in the other. Six patients had a myeloid blastic crisis (BC), five a lymphoid BC, and the other two an erythroid and an undifferentiated BC, respectively. All patients with myeloid BC and the one with undifferentiated BC disclosed a progressive expansion of the clone with p53 loss that was associated with a significant reduction in apoptosis. On the contrary in the 5 patients with lymphoid BC no significant p53 LOA rate was observed during the course of the disease. In these patients apoptotic process also persisted in the acute phase although in a lower rate as compared to CP.
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PMID:p53 loss and point mutations are associated with suppression of apoptosis and progression of CML into myeloid blastic crisis. 930 15

In chronic myeloid leukaemia (CML), as with other tumour types, mutations of the p53 gene are associated with disease progression. Changes in regional methylation of DNA with CML tumour development have also been demonstrated. Methylation is one mechanism by which gene expression is controlled and the CpG sites, which are the targets of DNA methylation, are also the sites of a number of the mutations found in the p53 gene. Cells harbouring mutant p53 have been shown to accumulate further genomic and genetic aberrations and methylation which alters the conformation of DNA is also believed to play a role in genomic stability. There appears to be an interplay between p53 deregulation and changing methylation patterns with the progression of CML. The cause and effect of changes in both of these critical gene regulating, DNA repair and genomic stability factors and their deviation during the progression of CML will be discussed.
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PMID:p53 mutations, methylation and genomic instability in the progression of chronic myeloid leukaemia. 932 84

Clinical studies have indicated that folate deficiency may enhance the development of various malignancies. In animal studies that examined the effect of folate deficiency on malignancies, conflicting results have been reported. In some studies, folate deficiency increased the development and growth of malignant tumors; in others, it decreased the development and growth of malignancies. We examined the effect of transient folate deficiency on the development of leukemia in mice infected with the anemia-inducing strain of Friend leukemia virus. Friend virus disease can be considered as a model for human acute leukemias that are preceded by a preleukemic period. These include leukemias that develop in patients who received previous chemotherapy and/or radiation therapy, as well as patients with chronic granulocytic leukemia or myelodysplasia. Folate deficiency around the time of Friend virus-infection delayed the onset but increased the incidence of leukemia. The rates of rearrangement of the Spi-1 (PU.1 ) oncogene by provirus integration and alteration of the p53 tumor-suppressor gene were the same in leukemia cell lines derived from folate-deficient mice as they were in cell lines from control mice. These results indicate that folate deficiency did not exert its enhancement of leukemogenesis through changes in either Spi-1 or p53, even though these two genes have been found to be the most frequently altered ones in Friend virus-induced leukemias. Our results suggest that folate deficiency may enhance the development of acute leukemia in patients who are at high risk for this disease.
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PMID:Folate deficiency delays the onset but increases the incidence of leukemia in Friend virus-infected mice. 935 75

We have identified three unbalanced translocations involving chromosomes 5 and 17, der(5)t(5;17), der(17)t(5;17), and dic(5;17), in the malignant cells from 17 patients with myeloid neoplasms. Six patients had a primary myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) de novo; ten patients had therapy-related MDS and/or AML (t-MDS/t-AML), and one patient had chronic myelogenous leukemia in myeloid blast phase. Two of the six patients with MDS or AML de novo had extensive exposure to industrial solvents, and one patient had Seckel syndrome. The primary diagnoses for the ten patients with t-MDS/t-AML were breast carcinoma and Hodgkin's disease in two patients each, and non-Hodgkin's lymphoma, multiple myeloma, chronic lymphocytic leukemia, ovarian carcinoma, thyroid carcinoma, and rhabdomyosarcoma in one patient each. Four patients had received both prior chemotherapy and radiotherapy, four others received prior chemotherapy only, and the remaining two patients only prior radiotherapy. Fluorescence in situ hybridization of centromere-specific probes for chromosomes 5 and 17 revealed that a dicentric rearrangement was the most common (13/16 patients examined). The genetic consequences of these chromosomal rearrangements are partial monosomy for 5q and 17p. Two of six patients examined had point mutations in TP53, suggesting that loss of function of TP53 in addition to loss of a tumor suppressor gene on 5q may be involved in the pathogenesis of the malignant disease in some of these patients.
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PMID:dic(5;17): a recurring abnormality in malignant myeloid disorders associated with mutations of TP53. 936 36

Cell cycle control subsequent to gamma irradiation or growth factor starvation has been studied in immative hematopoietic cells of 19 previously untreated chronic myeloid leukemia (CML) patients in chronic phase compared with 18 normal controls. CD34-positive cells were cultured for seven days in the presence of optimal concentrations of appropriate growth factors. At day 7 of culture both S-phase fraction and differentiation were identical in normal and leukemic cells. In normal cells the proportion of S-phase cells was reduced by irradiation with 500 rad from 40 +/- 3% to 16 +/- 2%. In contrast, in CML cells a reduction of S-phase cells from 35 +/- 2% to 25 +/- 3% was observed. Moreover, irradiated CML cells arrested at a smaller number of cells in G2. Similarly, a significantly higher proportion of CML cells remained in S phase after withdrawal of growth factors. Semiquantitative PCR of p21 (waf1/cip1) induction by gamma irradiation provided no evidence for a major functional deficiency of p53 response to irradiation in these cells. Our results demonstrate an abnormal cell cycle arrest in chronic-phase CML cells both after gamma irradiation and after growth factor removal. This observation might have important implications for understanding the pathogenesis of both hyperplasia of chronic phase and the development of blast crisis in CML. The molecular mechanisms underlying these abnormalities in bcr-abl-positive cells remain to be clarified.
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PMID:Deficient cell cycle control in myeloid cells of patients with newly diagnosed chronic myeloid leukemia. 938 81

The TP53 gene has been extensively studied in patients with chronic myeloid leukemia (CML), both in chronic phase and in blast crisis. Mutations in the gene were found in up to 30% of the patients, especially among those in blast crisis. We report the results of an analysis of 29 blood samples from CML patients: 8 samples from chronic phase patients, 8 from patients in the accelerated phase, and 13 from patients in blast crisis. By using genomic DNA, we sequenced PCR products of the coding exons and most introns of the TP53 gene, finding genetic changes in 30% of the blast crisis samples and 12% in chronic phase. All mutations were found in introns and were previously unreported. Immunocytochemical studies revealed accumulation of TP53 in blood cells of samples both from chronic phase and blast crisis patients. Since these samples had no TP53 mutations, we believe that wild type TP53 accumulates in blood cells of CML patients. Our results, therefore, indicate that molecular changes in coding regions of the TP53 gene are rare. The significance of the abundance of intronic changes should be investigated further. Accumulation of wild type TP53 in CML cells may indicate an additional mechanism involving this gene in the pathogenesis of this disease.
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PMID:Molecular alterations in the TP53 gene of peripheral blood cells of patients with chronic myeloid leukemia. 944 36

We present here a rare case of Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia having p190 BCR/ABL with a malignant clinical picture of extramedullary blast crisis at onset, followed by rapid evolution to bone-marrow blast crisis. The patient was a 44-year-old woman presenting with leukocytosis and multiple lymph-node swelling in the neck. Lymph-node biopsy revealed a myeloperoxidase-positive blastoma with cell-surface markers of myeloid and T-lymphoid lineages. Fluorescence in situ hybridization and the reverse transcription polymerase chain reaction detected a minor BCR breakpoint but failed to detect a major BCR breakpoint. By single-strand conformation polymorphism and direct sequencing, no alteration in the TP53 gene was found, and no additional chromosomal abnormalities other than Ph were identified. The present case suggests that p190 BCR/ABL is associated with the aggressive course of the disease.
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PMID:Extramedullary presentation of chronic myelogenous leukemia with p190 BCR/ABL transcripts. 953 Mar 44


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