Fig. 4.

The underlying mechanism of etoposide induced therapy-related leukemia. TOP2 is an essential as well as a genotoxic enzyme. Typically, the TOP2, DNA, and TOP2-DNA complex are maintained precisely to perform the relevant cellular functions. If the TOP2 enzyme activity is insufficient, the TOP2-DNA complex is lacking, resulting in the inability to release the torsional stress, leading to cell division failure and eventual death due to the failure to unwind the daughter chromosomes. In contrast, TOP2 poisons inactivate the enzymes via interfacial or covalent interaction, resulting in irreversible damage to the TOP2-DNA complex and ultimately creating DSB. Accumulation of DSB inhibits fundamental DNA processes and initiates recombination/repair pathways that produce chromosomal translocations and mutations. If the DSB overwhelms the cells, they will trigger apoptosis, which is the primary anticancer mechanism of etoposide. If the concentration of TOP2 mediated DSB is limited to induce apoptosis, mutations or chromosomal aberrations could occur, and it is possible to develop cancers. Etoposide caused therapy-related leukemia is a chromosomal rearrangement involving the MLL gene on chromosome 11q23. Meantime, etoposide quinone inhibits CREBBP or TCPTP, which has been reported to be associated with leukemogenesis.