Specific chromosomal mutagenesis observed in stimulated lymphocytes from patients with S‐ANLL

Mamuris, Zissis; Dumont, Jeanine; Dutrillaux, Bernard; Aurias, Alain

doi:10.1002/ijc.2910460402

Cited by 9 publications

(4 citation statements)

References 35 publications

(28 reference statements)

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“…Previous in vitro studies have shown that melphalan preferentially induces breaks and structural aberrations in chromosomes 5, 7, 11 and 17 (8)(9)(10). Deletion of 5q31 was also detected in multiple myeloma patients treated with melphalan (11).…”

Section: Introductionmentioning

confidence: 81%

Leukaemia-specific chromosome damage detected by comet with fluorescence in situ hybridization (comet-FISH)

et al. 2007

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Acute myeloid leukaemia (AML) is associated with exposure to benzene and treatment with chemotherapeutic agents. It is thought to arise from damage to specific regions of DNA, resulting in chromosome rearrangements or loss. For instance, a deletion on the long arm of chromosome 5 [e.g. del(5q31)] is common in AML patients previously treated with alkylating agents, such as melphalan, or exposed to benzene. Translocations of the MLL gene at 11q23 are frequently observed in AML arising from treatment with topoisomerase II inhibitors, such as etoposide. Our goal was to determine whether or not breakage at 5q31 and 11q23 is selectively induced by these chemical agents. To address this question, the comet assay combined with fluorescence in situ hybridization (comet-FISH) was used to detect DNA breakage in the specific chromosomal regions in an in vitro model. TK6 lymphoblastoid cells were exposed to melphalan, etoposide or the benzene metabolite, hydroquinone (HQ), at various concentrations. HQ, melphalan and etoposide induced DNA breaks at both 5q31 and 11q23 chromosome regions in a dose-dependant manner. However, HQ produced significantly more DNA damage at 5q31 than at 11q23. Etoposide produce slightly more DNA damage at 11q23 and melphalan had a somewhat greater effect at 5q31, but not significantly so. Thus, HQ and melphalan act similarly, perhaps explaining some similarities between benzene- and alkylating agent-induced AML. Comet-FISH also appears to be a useful approach for detecting and comparing damage to specific chromosome regions of significance in leukaemogenesis.

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Section: Introductionmentioning

confidence: 81%

Leukaemia-specific chromosome damage detected by comet with fluorescence in situ hybridization (comet-FISH)

et al. 2007

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“…That these benzene-induced and leukemia-relevant aneuploidies occur in healthy workers with current exposure to benzene as demonstrated in the present study, as well as in benzene-related leukemia and preleukemia patients (9), suggests that aneuploidy precedes and may be a potential mechanism underlying benzene-induced leukemia. Aneuploidy of chromosomes 5 and 7 may also be a mechanism underlying therapy-related AML cases, which arise after treatment with the alkylating drugs such as melphalan (35,36).…”

Section: Discussionmentioning

confidence: 99%

Chromosome-wide aneuploidy study (CWAS) in workers exposed to an established leukemogen, benzene

Zhang¹,

Lan

Guo³

et al. 2011

Carcinogenesis

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Evidence suggests that de novo, therapy-related and benzene-induced acute myeloid leukemias (AML) occur via similar cytogenetic and genetic pathways, several of which involve aneuploidy, the loss or gain of chromosomes. Aneuploidy of specific chromosomes has been detected in benzene-related leukemia patients as well as in healthy benzene-exposed workers, suggesting that aneuploidy precedes and may be a potential mechanism underlying benzene-induced leukemia. Here, we analyzed the peripheral blood lymphocytes of 47 exposed workers and 27 unexposed controls using a novel OctoChrome fluorescence in situ hybridization (FISH) technique that simultaneously detects aneuploidy in all 24 chromosomes. Through this chromosome-wide aneuploidy study (CWAS) approach, we found heterogeneity in the monosomy and trisomy rates of the 22 autosomes when plotted against continuous benzene exposure. In addition, statistically significant, chromosome-specific increases in the rates of monosomy [5, 6, 7, 10, 16 and 19] and trisomy [5, 6, 7, 8, 10, 14, 16, 21 and 22] were found to be dose dependently associated with benzene exposure. Furthermore, significantly higher rates of monosomy and trisomy were observed in a priori defined 'susceptible' chromosome sets compared with all other chromosomes. Together, these findings confirm that benzene exposure is associated with specific chromosomal aneuploidies in hematopoietic cells, which suggests that such aneuploidies may play roles in benzene-induced leukemogenesis.

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“…Similarly, Morad and El Zawahri [1977] showed a nonrandom distribution of cyclophoshamide-induced chromosome breaks. Then, in a series of classic studies, Mamuris et al showed that the leukemogenic drug melphalan caused selective damage to chromosomes 5, 7, 11, and 17 both in vitro [Mamuris et al, 1989b] and in patients treated with this alkylating agent [Mamuris et al, 1989a[Mamuris et al, , 1990. Further, Sasiadek [1992] has suggested that benzene causes more breaks in certain chromosomes than in others.…”

Section: Discussionmentioning

confidence: 99%

Nonrandom aneuploidy of chromosomes 1, 5, 6, 7, 8, 9, 11, 12, and 21 induced by the benzene metabolites hydroquinone and benzenetriol

Zhang

Yang

Hubbard

et al. 2005

Environ. Mol. Mutagen.

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The loss and gain of whole chromosomes (aneuploidy) is common in the development of leukemia and other cancers. In acute myeloid leukemia, the loss (monosomy) of chromosomes 5 and 7 and the gain (trisomy) of chromosome 8 are common clonal chromosomal abnormalities. Here, we have tested the hypothesis that metabolites of the human leukemogen benzene cause a higher rate of gain and loss among the chromosomes involved in leukemogenesis and, as such, are nonrandom and selective in their effects. Human peripheral blood was exposed to two metabolites of benzene, namely, hydroquinone (HQ) and benzenetriol (BT), and the ploidy status of nine different chromosomes (1, 5, 6, 7, 8, 9, 11, 12, and 21) was examined using fluorescence in situ hybridization of metaphase spreads. Poisson regression was used to provide interpretable incidence rate ratios and corresponding P values for all nine chromosomes. Statistically significant differences were found between the sensitivity of the nine chromosomes to gain or loss. Chromosomes 5 and 7 were highly sensitive to loss following HQ and BT exposure, whereas chromosomes 7, 8, and 21 were highly sensitive to gain in comparison to other chromosomes. Significant support for the a priori hypothesis that chromosomes 5 and 7 are more sensitive to loss induced by HQ and BT than the other seven chromosomes was also obtained. These data support the notion that benzene metabolites affect the ploidy status of specific chromosomes more than others and may initiate or promote leukemia induction through these specific effects.

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Specific chromosomal mutagenesis observed in stimulated lymphocytes from patients with S‐ANLL

Cited by 9 publications

References 35 publications

Leukaemia-specific chromosome damage detected by comet with fluorescence in situ hybridization (comet-FISH)

Leukaemia-specific chromosome damage detected by comet with fluorescence in situ hybridization (comet-FISH)

Chromosome-wide aneuploidy study (CWAS) in workers exposed to an established leukemogen, benzene

Nonrandom aneuploidy of chromosomes 1, 5, 6, 7, 8, 9, 11, 12, and 21 induced by the benzene metabolites hydroquinone and benzenetriol

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