Abstract
Malignant transformation depends on the accumulation of gene mutation that is important for cell growth, tumor suppression and cell cycle regulation. However, it takes decades to accumulate these mutations in adult cancer. In the cancer prone genetic disorders, cell cycle regulatory genes such as p53, BRCA1 and ATM are mutated. Recent clinical observations have revealed that leukemogenesis in childhood leukemia occurs already in intrauterine period.
So called "infant leukemia" which occurs in less than one year-old children has MLL(Mixed Lineage Leukemia/Myeloid Lymphoid Leukemia)gene rearrangement frequently. This rearrangement also observed in secondary leukemia and break point is clustered in 8.3kbp of 90kbp MLL gene in both cases. In this breakpoint cluster region (BCR), topoisomeraseII(TopoII) binding sites are known to be clustered.
TopoII is essential for structural maintenance of genomic DNA in cell metabolism, and forms a covalent linkage to both strands of DNA helix, makes a transient double-strand break (DSB) in the helix, and re-ligates the cleaved DNA. The agents with TopoII inhibitory activity such as etoposide, induce DNA DSBs by stabilizing covalent TopoII-DNA complexes and thereby exert their function as anticancer drug by inducing apoptosis. Exposure to bioflavonoid with TopoII inhibitory activity, which is contained in food also induces DSBs in BCR in MLL gene in vitro.
We have recently reported that early G2/M checkpoint failure is a risk factor for etoposide-induced chromosomal aberrations in vitro. Furthermore, we have shown reduction of p53ser15 phosphorylation in normal peripheral lymphocytes after ionizing radiation in two out of seven infant leukemia patients. In one case, we have found heterozygote ATM mutation that has dominant negative effect in vitro. These observation indicate that exposure to agents with TopoII inhibitory activity and G2/M checkpoint failure could be a molecular mechanism for leukemogenesis.
