• Borgers, Susanne
• Strissel, Pamela L.
• Strick, Reiner
• Rowley, Janet D.
• Smith, Steve L.

Abstract

<jats:p>Chromosomal translocations involving the<jats:italic>MLL</jats:italic>gene occur in about 80% of infant leukemia. In the search for possible agents inducing infant leukemia, we identified bioflavonoids, natural substances in food as well as in dietary supplements, that cause site-specific DNA cleavage in the<jats:italic>MLL</jats:italic>breakpoint cluster region (BCR)<jats:italic>in vivo</jats:italic>. The<jats:italic>MLL</jats:italic>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<jats:italic>MLL</jats:italic>BCR cleavage site induced by chemotherapeutic agents, such as etoposide (VP16) and doxorubicin (Dox). Both<jats:italic>in vivo</jats:italic>and additional<jats:italic>in vitro</jats:italic>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 topo II-induced DNA cleavage. Reversibility experiments demonstrated a religation of the bioflavonoid as well as the VP16-induced<jats:italic>MLL</jats:italic>cleavage site. Our observations support a two-stage model of cellular processing of topo II inhibitors: The first and reversible stage of topo II-induced DNA cleavage results in DNA repair, but also rarely in chromosome translocations; whereas the second, nonreversible stage leads to cell death because of an accumulation of DNA damage. These results suggest that maternal ingestion of bioflavonoids may induce<jats:italic>MLL</jats:italic>breaks and potentially translocations<jats:italic>in utero</jats:italic>leading to infant and early childhood leukemia.</jats:p>

Topics

• cluster
• experiment