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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In experimental models, leukemia was the first disease shown to have an association with the major histocompatibility complex (MHC) genes. In humans, several allelic human-leukocyte antigen (HLA) associations also have been recognized. In addition to allelic associations, atypical HLA segregation patterns have been observed in leukemic families. These include a higher frequency of HLA-identical unaffected siblings, increased HLA homozygosity and increased maternal HLA-DR identity. These observations suggest preferential transmission of disease-associated haplotypes and a male transmission bias in leukemic families. The lack of disease-specific segregation, however, supports the idea that the HLA system is not directly relevant in leukemogenesis. Therefore, the existence of another genetic region linked to the MHC, causing segregation distortion, and containing recessive leukemia susceptibility genes may be postulated. The mouse t-complex would fit this model. This gene complex has recessive (semi-) lethal genes, is transmitted preferentially through fathers, and both the mouse t-complex and its rat homolog, growth and reproduction complex grc, confer susceptibility to carcinogenesis. This model could also explain the increased spontaneous abortion rate in mothers of leukemic patients, epidemiologic associations of leukemia with oral clefts and neuroectodermal tumors, and the transmission of a radiation-induced leukemia risk through fathers. Such segregation distortion might be the reason behind the maintenance of a gene(s) with a lethal effect in the population.
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PMID:Major histocompatibility complex, t-complex, and leukemia. 161 Sep 74

Previous studies have revealed marked differences in the pattern of carcinogenesis between rats and mice exposed to 1,3-butadiene (BD) that do not appear to be readily explained on the basis of pharmacokinetics or metabolism. Chronic exposure of B6C3F1 mice to BD produces a high incidence of thymic lymphoma (TL) that is not observed in rats. The potential of the endogenous ecotropic retroviral background to influence susceptibility to BD leukemogenesis was examined by comparing the incidence of TL between B6C3F1 and NIH swiss mice. Proviral ecotropic sequences are truncated in the NIH Swiss mouse, and the virus is not expressed. Chronic exposure to BD (1250 ppm) for up to 1 year resulted in a fourfold difference in the incidence of TL between B6C3F1 (57%) and NIH Swiss (14%) mice. These results provide presumptive evidence for retrovirus involvement since NIH Swiss mice lack ecotropic viruses and appear to be relatively resistant to induction of lymphoma by BD.
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PMID:Susceptibility to 1,3-butadiene-induced leukemogenesis correlates with endogenous ecotropic retroviral background in the mouse. 255 16

We have examined the spleen DNA of individual mice of the RFM/Un strain for evidence of re-integration of the endogenous ecotropic provirus in radiation-induced and spontaneous neoplasms. The ecotropic env specific probe detects only a single 19 kb EcoRI or a single 7.0 kb HindIII fragment in all DNA preparations from normal tissues of RFM mice, corresponding to the endogenous provirus. Additional DNA restriction fragments containing the ecotropic virus (eco) specific sequence, corresponding to somatically acquired provirus, are detected in two out of five spleen DNA samples from animals with myeloid leukemia and one of three with thymic lymphoma. In addition somatically acquired eco-specific fragments are also detected in greater than 85% of DNA samples from reticulum cell sarcomas, a late occurring spontaneous hematopoietic neoplasm in this mouse strain. These results are consistent with a 'promoter/enhancer insertion' model of leukemogenesis involving the endogenous ecotropic provirus and are of particular interest since the RFM/Un mouse possesses a locus that restricts exogenous infection of cells by the endogenous virus.
Carcinogenesis 1986 Apr
PMID:Hematopoietic neoplasias of the RFM/Un mouse contain somatic re-integration of the restriction endogenous ecotropic provirus. 300 44

The detection and characterization of oncogenes via RNA tumor viruses (or retroviruses) and the recognition of their location at breakpoints of chromosomal translocations which are frequently found in certain human neoplasms has promoted present understanding of molecular mechanisms underlying carcinogenesis. Oncogenes are cellular genes which can be transduced by RNA tumorviruses and induce malignant transformation under experimental conditions in vivo and in vitro. A role of retroviruses in human leukemogenesis is suggested by epidemiological observations and by the isolation of such viruses from several human T-cell leukemias and lymphomas (human T-cell leukemia/lymphoma virus or HTLV) as well as by biochemical association of retroviral markers with human leukemias. A role of HTLV has been suggested also in a human immune deficiency syndrome (AIDS). In view of the well known role of many factors in carcinogenesis the concept of carcinogenesis as a multistep process as well as the concept of cocarcinogenesis and the role of cofactors other than viruses, such as radiation and chemicals, aging, hormones, graft vs host reaction, environmental factors etc., will have to be carefully considered.
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PMID:RNA-tumorviruses, oncogenes, and their possible role in human carcinogenesis. 631

Acute myeloid leukemia or one of its variants is being reported with increasing frequency as a second neoplasm in patients being treated for multiple myeloma, Hodgkin's disease, non-Hodgkin's lymphoma and a variety of other primary neoplasms and non-neoplastic diseases. Although many of these patients were treated with both chemotherapy and radiotherapy, many received no radiotherapy at all. Drugs most frequently implicated in the causation of acute leukemia and other second neoplasms are the alkylating agents, procarbazine and the nitrosoureas. The frequency of this syndrome varies from less than 1 per cent to 7 per cent in many reported series of patients. There could develop a reluctance to use cytotoxic agents to treat malignant neoplasms for fear of inducing acute leukemia. Although one has to consider this complication, one should not, however, withhold these drugs from a patient with a neoplasm or other potentially fatal disease in whom such therapy is the treatment of choice. We seem to be faced with the paradox that patients benefiting most from chemotherapy may be at highest risk of suffering its undesirable consequences. Although the risk of leukemogenesis or carcinogenesis in man may be small, these drugs should be used with caution in patients with indolent non-neoplastic diseases such as rheumatoid arthritis.
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PMID:Cancer and secondary leukemia. 657 7

There is increasing evidence that the supportive cells (stromal cells) in nearly all organs containing cellular self-renewal systems are involved in carcinogenesis. One body of evidence specific to irradiation leukemogenesis documents the role of irradiated murine stromal cells in the cell biologic changes associated with evolution of leukemia in cocultivated, nonirradiated stem cells. Stem cell phenotypic changes that have been documented include upregulation of cell surface c-fms, downregulation of growth requirement for obligatory growth factors, and the appearance of novel transcripts detected by differential display. A second body of evidence documents the potential role of stromal cells functioning as biologic tumor promoters through their release of reactive oxygen species (ROS), and production of altered adhesion molecules or growth factors during the chronic response to chemical or physical carcinogens. These molecular biologic mechanisms, potentially operative in stromal cells, can block apoptosis and induce DNA strand breaks in closely associated self-renewing stem cells. In an in vivo model of irradiation effects on lung stromal cells, we have irradiated the lungs of control C57BL/6J mice or other mice with orthotopic Lewis lung tumors and shown that TGF-beta release is increased following irradiation. The TGF-beta increase by irradiation may specifically be inhibited by administering an inhalation plasmid liposome mixture containing a transgene for human manganese superoxide dismutase prior to irradiation. An appreciation of the role of stromal cells in leukemogenesis and carcinogenesis may also be very relevant to the design of new therapeutic strategies for treatment of cancer, particularly since current strategies focus on eradication of stem cell transformants and do not rigorously address the persistence of surviving stromal cells.
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PMID:Stromal cell involvement in leukemogenesis and carcinogenesis. 872 6

The His-1 gene is expressed as a 3-kb spliced and polyadenylated RNA that is believed to function in the absence of an encoded protein. The precise function of the His-1 gene is unknown, but its transcriptional activation in a series of mouse leukemias has implicated the His-1 RNA in leukemogenesis when it is abnormally expressed. To study the oncogenic potential of this gene in more detail, we have examined the normal tissue distribution of His-1 RNA during mouse embryogenesis and in various adult tissues. His-1 expression was detected at low levels in the epithelia of the adult mouse stomach, prostate, seminal vesicle, and the developing choroid plexus by in situ hybridization. All other tissues examined lacked detectable levels of hybridizing RNA, suggesting that normal His-1 gene expression is highly restricted to these epithelial sites. These transcripts were not detectable by Northern blot analysis of normal tissues but were readily identified in five mouse leukemias and in five carcinomas of the choroid plexus. These data indicate that the His-1 gene expression is highly restricted and suggest that inappropriate activation of this gene may contribute to carcinogenesis.
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PMID:Expression of the putative proto-oncogene His-1 in normal and neoplastic tissues. 909 86

The hematotoxicity of benzene, a human leukemogen, has been postulated to be mediated by reactive metabolites and involve cell damage caused by reactive oxygen species. Because expression of the transcription factors AP-1 and NF-kappaB is sensitive to the redox state in eukaryotic cells, the DNA binding activity of AP-1 and NF-kappaB was examined in HL-60 promyeloid leukemia cells exposed to trans,trans-muconaldehyde, a microsomal hematotoxic metabolite of benzene. There was little AP-1 binding activity in nuclear extracts from control HL-60 cells based on electrophoretic mobility shift assays. Exposure to 0.1 microM MUC for 4 h resulted in significantly increased levels of nuclear protein with high sequence specificity for the consensus AP-1 sequence. In addition, electrophoretic mobility shift assays showed a strong increase in the binding of a factor to the NF-kappaB site. The latter was highest in nuclear extracts from HL-60 cells treated with 1.0 microM muconaldehyde and cultured for 4 h. Exposure of HL-60 cells to muconaldehyde resulted in an increase in c-fos and c-jun mRNA levels. Western blot analysis showed that the protein levels of c-jun increased in HL-60 cells treated with 1 microM muconaldehyde and cultured for 4-6 h and subsequently decreased gradually. Increased AP-1 binding was observed in bone marrow cells from B6C3F1 mice 2 h after administration of 440 mg/kg benzene. We suggest that increased gene expression of NF-kappaB and AP-1 binding activity and up-regulation of c-fos and c-jun may play a role in the mechanism of benzene leukemogenesis.
Carcinogenesis 1997 Apr
PMID:Increased gene expression in human promyeloid leukemia cells exposed to trans,trans-muconaldehyde, a hematotoxic benzene metabolite. 911 Dec 8

Leukemias are monoclonal diseases that arise from cells in the hematopoietic stem and progenitor cell compartment. Consistent with emerging models of carcinogenesis, leukemogenesis is an evolutionary process that involves multiple independent genetic and epigenetic events. Over the last half-century a predominant paradigm has emerged to describe leukemia developing secondary to alkylating drug therapy or exposure to benzene in which progressive dysplastic changes, accompanied by a distinct pattern of clonal cytogenetic abnormalities, give rise to acute myelogenous leukemia. Characterization of these clonal chromosomal aberrations, together with observed alterations in other growth-promoting genes, provides a useful framework for studying chemical leukemogenesis and for use in understanding the origins and development of leukemia in general.
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PMID:The process of leukemogenesis. 911 99

The 7,12-dimethylbenz[a]anthracene (DMBA)-induced rat leukemia model enables scientists to analyze cells altered by carcinogens at various stages of leukemogenesis. We have reported that a consistent type of point mutation. A-->T transversion at the second base in codon 61 of the N-ras gene, was present in this leukemia and that this mutation appeared in bone marrow cells as early as 48 h after a single dose of DMBA. In addition, two leukemia cell lines with the N-ras mutation had no wild-type N-ras allele. Therefore, we examined whether these alterations were essential to the DMBA-induced leukemias. In the study reported here, we confirmed the occurrence of this N-ras mutation in 18 (86%) of 21 primary leukemias and loss of the N-ras wild-type allele in 12 (67%) of 18 leukemias with the mutated N-ras. By using microsatellite markers on chromosome 2, loss of heterozygosity (LOH) at the N-ras locus was observed in eight leukemias, all of which were shown to have lost the wild-type N-ras allele by mutant-allele-specific amplification. These results suggest that LOH related to loss of the wild-type N-ras allele reproducibly occurs in leukemias with the N-ras mutation. Considering the timing of the N-ras mutation and LOH, it is likely that the N-ras mutation is induced early, and cells that have lost the wild-type N-ras allele seem to develop into leukemia. We believe that this system provides a suitable model for studying a series of genetic alterations from the earliest stage of carcinogenesis that cannot be approached in human malignancies.
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PMID:Loss of heterozygosity at the N-ras locus in 7,12-dimethylbenz[a] anthracene-induced rat leukemia. 914 15


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