Common dietary and environmental compounds promote a leukemic translocation in hematopoietic stem cells and differentiated cells

Maternal exposure to topoisomerase II (topoII) inhibitors that are biochemically similar to the chemotherapeutic drug etoposide may promote infant acute leukemia. Several studies have shown that common dietary bioflavonoids as well as benzene metabolites can induce DNA double strand breaks (DSB) and inhibit topoII. The goal of this study was to determine the relative potential for bioflavonoids genistein and quercetin, and possible leukemogenic compounds p-benzoquinone and dipyrone to promote rearrangements between the MLL and AF9 breakpoint cluster regions within specific hematopoietic cell subpopulations. A murine embryonic stem (ES) cell line containing two Green Fluorescent Protein (GFP) DSB-inducible recombination reporter substrates was differentiated in vitro into embryoid bodies (EB) containing hematopoietic stem cells (HSC) followed by differentiation into myeloid progenitor subpopulations. Following exposure to genistein, quercetin, p-benzoquinone, or dipyrone at each of three developmental stages, the frequency of interchromosomal translocations between the MLL-AF9 bcrs was determined as well as the mechanism used for repair. Bioflavonoids genistein and quercetin were the strongest inducers of translocations during the earliest stage of differentiation. The frequency of translocations induced by each of these compounds at later stages of differentiation was dramatically reduced. The results demonstrate that all four compounds promote translocations between the MLL and AF9 bcrs at different stages of differentiation and ES cells are particularly susceptible.