Topo II

Topoisomerase II (Topo II) is a nuclear enzyme that modulates DNA topology by inducing transient double-strand breaks and facilitating chromosomal segregation during mitosis^[1][2]. Mechanistically, Topo IIα primarily associates with proliferating cells, regulating cell division, whereas Topo IIβ participates in differentiation and transcriptional regulation^[2][3]. In disease contexts, aberrant Topo II activity or inhibition can induce DNA double-strand breaks, contributing to infant leukemia through MLL gene rearrangements during fetal development^[4][5]. Clinical evidence indicates that inhibitors of Topo II, such as anthracyclines, selectively target Topo IIα to exert cytotoxic effects in hematological malignancies, but off-target inhibition of Topo IIβ mediates cardiotoxicity^[6][7]. Compared with Topo IIα, Topo IIβ displays distinct expression patterns and immunophenotype associations in acute myeloid leukemia, reflecting unique biological roles^[3]. Isoform-specific inhibitors, such as topobexin, exploit structural differences in the ATPase domains of Topo IIα and Topo IIβ, enabling selective inhibition of Topo IIβ and protection against anthracycline-induced cardiac damage^[7]. Mechanistic studies further reveal that cellular resistance to Topo II inhibitors involves post-translational modifications, including phosphorylation, and signaling pathways that modulate DNA damage responses^[2]. Collectively, these findings highlight Topo II isoforms as critical molecular targets with distinct functional roles, disease relevance, and therapeutic implications for selective drug design^[2][7].