Topoisomerase II and leukemia

Abstract

Type II topoisomerases are essential enzymes that modulate DNA under- and overwinding, knotting, and tangling. Beyond their critical physiological functions, these enzymes are the targets for some of the most widely prescribed anticancer drugs (topoisomerase II poisons) in clinical use. Topoisomerase II poisons kill cells by increasing levels of covalent enzyme-cleaved DNA complexes that are normal reaction intermediates. Drugs such as etoposide, doxorubicin, and mitoxantrone are frontline therapies for a variety of solid tumors and hematological malignancies. Unfortunately, their use also is associated with the development of specific leukemias. Regimens that include etoposide or doxorubicin are linked to the occurrence of acute myeloid leukemias that feature rearrangements at chromosomal band 11q23. Similar rearrangements are seen in infant leukemias and are associated with gestational diets that are high in naturally occurring topoisomerase II-active compounds. Finally, regimens that include mitoxantrone and epirubicin are linked to acute promyelocytic leukemias that feature t(15;17) rearrangements. The first part of this article will focus on type II topoisomerases and describe the mechanism of enzyme and drug action. The second part will discuss how topoisomerase II poisons trigger chromosomal breaks that lead to leukemia and potential approaches for dissociating the actions of drugs from their leukemogenic potential.

Keywords: acute myeloid leukemia; acute promyelocytic leukemia; anticancer drug; chromosomal translocation; topoisomerase II poison.

Figure 1

Topoisomerase II is an essential but genotoxic enzyme. The balance between enzyme-mediated DNA cleavage (which is required for its physiological functions) and ligation is critical for cell survival. If the level of topoisomerase II–mediated DNA cleavage decreases below threshold levels, cells are not able to untangle daughter chromosomes and ultimately die of mitotic failure (left). If the level of cleavage becomes too high (right), the actions of DNA-tracking systems can convert these transient complexes to permanent double-stranded breaks. The resulting DNA breaks, as well as the inhibition of essential DNA processes, initiate recombination/repair pathways and generate chromosome translocations and other DNA aberrations. If the strand breaks overwhelm the cell, they can trigger cell death. This is the basis for the actions of several widely prescribed anticancer drugs. If cell death does not occur, mutations or chromosomal aberrations may be present in surviving populations. Exposure to topoisomerase II poisons is associated with the formation of specific types of t-AMLs and infant leukemias that involve the MLL (mixed lineage leukemia) gene at chromosome band 11q23 and t-APLs that feature t(15:17) chromosomal translocations between the PML (promyelocytic leukemia) and RARA (retinoic acid receptor α) genes (lower right arrow).

Figure 2

Structures of selected topoisomerase II poisons. Clinically used anticancer drugs that target topoisomerase II are shown on the left. Dietary topoisomerase II poisons are shown on the right. The catechol and quinone metabolites of etoposide (generated by CYP3A4 and cellular oxidases or redox cycling, respectively) are highlighted in the red box. Epigallocatechin gallate is abbreviated as EGCG.

Figure 3

Schematic of the MLL locus (chromosomal band 11q23) showing the breakpoint cluster region (BCR). Exons 8–14 are indicated by red rectangles. MLL breakpoints cluster within an 8-kb region of the gene (green line). Breakpoints observed in topoisomerase II–associated t-AMLs and infant AMLs are more tightly clustered in the ~ 1 kb telomeric end of the BCR (blue line). Adapted from Ref. .

Figure 4

Schematic of the PML locus (chromosomal band 15q22) showing the distribution of breakpoints within intron 6 (bcr1 breakpoint region) in t-APL. Exons 6 and 7 are indicated by red rectangles. Arrows denote PML translocation breakpoints identified in patients treated with mitoxantrone (black triangles) or epirubicin (green triangles). The asterisk denotes an 8–base pair breakpoint cluster hotspot observed in mitoxantrone-related t-APLs. A separate cluster was associated with epirubicin-related t-APLs. Chromosomal breakpoints are preferential sites of topoisomerase II cleavage induced by the respective drugs. Adapted from Ref. .