Carcinogenesis Advance Access originally published online on April 29, 2007
Carcinogenesis 2007 28(8):1703-1709; doi:10.1093/carcin/bgm102
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Dietary flavonoids induce MLL translocations in primary human CD34+ cells
1 Department of Health Risk Analysis and Toxicology, Nutrition and Toxicology Research Institute Maastricht, Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands, Department of Clinical Genetics
2 Department of Obstetrics and Gynecology, Academic Hospital Maastricht, PO Box 5800, 6202 AZ Maastricht, The Netherlands
* To whom correspondence should be addressed. Tel: +31 43 3881103; Fax: +31 43 3884146;Email: s.khosrovani{at}grat.unimaas.nl
Genetic abnormalities leading to infant leukemias already occur during fetal development and often involve rearrangements of the mixed-lineage leukemia (MLL) gene. These rearrangements resemble the aberrations observed in therapy-related leukemias following treatment with topoisomerase II (topoII)-inhibiting agents such as etoposide. Since flavonoids are potent topoII inhibitors, we examined the role of three widely consumed dietary flavonoids (quercetin, genistein and kaempferol) on the development of MLL rearrangements in primary human CD34+ cells. Using the neutral Comet assay, we demonstrated a dose-dependent double-strand break (DSB) formation after exposure to flavonoids. An incorrect repair of these DSBs resulted in chromosomal translocations that co-localized with those identified in infant leukemias. Most of these translocations were formed by microhomology-mediated end joining. Moreover, in all but one translocation, SINE/Alu or LINE/L1 repetitive elements were present in at least one side of the breakpoint junction. Beside MLL translocations, fluorescence in situ hybridization analysis demonstrated monosomy or trisomy of MLL in 8–10% of the quercetin-exposed CD34+ cells. Our study demonstrates that biologically relevant concentrations of flavonoids can induce MLL abnormalities in primary hematopoietic progenitor cells. This is particularly alarming knowing that the differences in metabolism and excretion rate between mother and fetus can lead to a higher flavonoid concentration on the fetal side. Therefore, it is important to raise public awareness and set guidelines for marketing flavonoid supplements to reduce the risk of infant leukemias.
Abbreviations: DMSO, dimethylsulfoxide; DSB, double-strand breaks; FISH, fluorescence in situ hybridization; MLL, mixed-lineage leukemia; PCR, polymerase chain reaction; topoII, topoisomerase II; wt, wild type
Received November 7, 2006; revised April 17, 2007; accepted April 19, 2007.
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