Schooten, “Dietary flavonoids induce MLL translocations in primary human CD34+ cells

Genetic abnormalities leading to infant leukemias already occur during fetal development and often involve rearrangements of the mixed-lineage leukemia (MLL) gene. These rearrangements re-semble the aberrations observed in therapy-related leukemias following treatment with topoisomerase II (topoII)-inhibiting agents such as etoposide. Since flavonoids are potent topoII inhib-itors, we examined the role of three widely consumed dietary flavonoids (quercetin, genistein and kaempferol) on the develop-ment of MLL rearrangements in primary human CD341 cells. Using the neutral Comet assay, we demonstrated a dose-dependent double-strand break (DSB) formation after exposure to flavo-noids. An incorrect repair of these DSBs resulted in chromosomal translocations that co-localized with those identified in infant leu-kemias. Most of these translocations were formed by microhomol-ogy-mediated end joining. Moreover, in all but one translocation