Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10721 (c-kit)
 6,575 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Benzene (bz) is a common environmental contaminant associated with increased risk of myeloid leukemia. Chronic bz exposure in vivo increases the frequency of aneuploid circulating lymphocytes in humans. However, there is no information about persistence of bz-associated aneuploidy in immature/primitive cells, at risk of leukemic transformation, after bz exposure in vivo. We explored the relationship between the induction and persistence of aneuploidy in primitive hemopoietic cells from mice that received oral doses of bz in vivo. Short- and long-term persistence of aneuploidy were evaluated in immature/primitive sub-populations (Lin(-)c-kit(+)Sca-1(+)), as well as lymphoid and myeloid cells, 6 days and 2-8 months after exposure. Mice receiving bz in a corn oil carrier, or corn oil alone, both have increased aneuploidy frequencies (1-5%, compared to <1% in untreated controls) in all sub-populations, 6 days after exposure. However, unlike bz-induced aneuploidy, corn oil-induced aneusomies are transient, with frequencies returning to background levels in lymphoid and myeloid cells, 9 weeks after exposure. The frequency (5-9%) of aneuploid lymphocytes and myeloid cells is higher at 9 weeks than at 6 days, suggesting that bz disrupts chromosomal segregation in differentiated cells and/or progenitors. About 8 months after bz exposure, the Lin(-)c-kit(+)Sca-1(+) sub-population contains up to 14% aneuploid cells with numerical chromosomal aberrations affecting chromosomes 2 or 11. These data demonstrate that bz induces DNA copy number changes in immature/primitive cells, and that these changes persist for long periods. Although, initial exposures are not leukemogenic, subsequent exposures of cells to genotoxins or oxidative radicals that induce additional genetic hits may increase the risk of transformation. The contribution of bz-induced aneuploidy in immature/primitive cells to leukemogenesis remains to be determined.
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PMID:Persistence of aneuploid immature/primitive hemopoietic sub-populations in mice 8 months after benzene exposure in vivo. 1128 6

Benzene-induced hematopoietic toxicity is an aryl hydrocarbon receptor (AhR)-related adverse effect that is not exhibited in AhR-knockout (KO) mice. In the hematopoietic system, the steady-state expression of AhRs is limited in the hematopoietic progenitor cells; thus, a hierarchical hematopoietic impairment starts from hematopoietic progenitor cells after benzene exposure. When one looks at wild-type recipient mice that have been lethally irradiated and repopulated with AhR-KO bone marrow cells, owing to reconstruction by the marrow from AhR-KO mice, no impairment is observed in the assay of granulo-macrophage colony-forming units (CFU-GMs) in the bone marrow after benzene exposure of the reconstituted mice. In contrast, in mature white blood cells concern, benzene-induced hematopoietic cytotoxicity is observed in the same reconstituted mice; however, this benzene-induced hematopoietic cytotoxicity in mature white blood cells is not induced in the case of AhR-KO mice repopulated with wild-type bone marrow cells after a lethal dose of irradiation. The mechanism of benzene-induced hematopoietic toxicity in the mature blood cells in AhR-KO mice is assumed to be based on metabolites such as phenol and hydroquinone derived from hepatic AhR. Thus, the former toxicity in mature white blood cells is assumed to be based on the metabolites of the wild-type hepatic AhR, whereas the latter lack of toxicity in mature blood cells in AhR-KO mice is due to the lack of benzene-induced metabolism in the liver. Global gene expression analysis of bone marrow cells after benzene exposure reveals that MEF2c, the functions of which are known to maintain lymphocyte differentiation and promote proliferation of hematopoietic progenitor cells, is commonly downmodulated not only in C57BL/6 but also in C3H/He mice. In response to these impairments of the hematopoietic progenitor cells and the niches, stochastic and reciprocal upregulations of integrin beta 2 and the Runx family are observed, which are known to stabilize hematopoietic niches during the steady-state. Direct observation of the hematopoietic progenitor cells, particularly the Lin(-)c-kit(+)Sca-1(+) (LKS) fraction, after benzene exposure revealed an increased amount of intracytoplasmic reactive oxygen species (ROS) detected by ROS-reacting dye as compared with other blood cell fractions.
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PMID:Benzene-induced bone-marrow toxicity: a hematopoietic stem-cell-specific, aryl hydrocarbon receptor-mediated adverse effect. 2003 30