Dietary bioflavonoids induce cleavage in the MLL gene and may contribute to infant leukemia

Chromosomal translocations involving the MLL gene occur in about 80% of inf ant leukemia. In the search for possible agents inducing infant leukemia, w e identified bioflavonoids. natural substances in food as well as in dietar y supplements, that cause site-specific DNA cleavage in the MLL breakpoint cluster region (BCR) in vivo. The MLL BCR DNA cleavage was shown in primary progenitor hematopoietic cells from healthy newborns and adults as well as in cell lines; it colocalized with the MLL BCR cleavage site induced by ch emotherapeutic agents, such as etoposide (VP16) and doxorubicin (Dox), Both in vivo and additional in vitro experiments demonstrated topoisomerase II (topo II) as the target of bioflavonoids similar to VP16 and Dox, Based on 20 bioflavonoids tested, we identified a common structure essential for top o II-induced DNA cleavage. Reversibility experiments demonstrated a religat ion of the bioflavonoid as well as the VP16-induced MLL cleavage site. Our observations support a two-stage model of cellular processing of topo II in hibitors: The first and reversible stage of topo II-induced DNA cleavage re sults in DNA repair, but also rarely in chromosome translocations; whereas the second, nonreversible stage leads to cell death because of an accumulat ion of DNA damage. These results suggest that maternal ingestion of bioflav onoids may induce MLL breaks and potentially translocations in utero leadin g to infant and early childhood leukemia.