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Event: 1252

Key Event Title

The KE title should describe a discrete biological change that can be measured. It should generally define the biological object or process being measured and whether it is increased, decreased, or otherwise definably altered relative to a control state. For example “enzyme activity, decreased”, “hormone concentration, increased”, or “growth rate, decreased”, where the specific enzyme or hormone being measured is defined. More help

Binding to (interferes with) topoisomerase II enzyme

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. The short name should be less than 80 characters in length. More help
Binding, topoisomerase II

Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. Note, KEs should be defined within a particular level of biological organization. Only KERs should be used to transition from one level of organization to another. Selection of the level of biological organization defines which structured terms will be available to select when defining the Event Components (below). More help
Level of Biological Organization
Molecular

Cell term

Further information on Event Components and Biological Context may be viewed on the attached pdf.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable. More help
Cell term
eukaryotic cell

Organ term

Further information on Event Components and Biological Context may be viewed on the attached pdf.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable. More help

Key Event Components

Further information on Event Components and Biological Context may be viewed on the attached pdf.Because one of the aims of the AOP-KB is to facilitate de facto construction of AOP networks through the use of shared KE and KER elements, authors are also asked to define their KEs using a set of structured ontology terms (Event Components). In the absence of structured terms, the same KE can readily be defined using a number of synonymous titles (read by a computer as character strings). In order to make these synonymous KEs more machine-readable, KEs should also be defined by one or more “event components” consisting of a biological process, object, and action with each term originating from one of 22 biological ontologies (Ives, et al., 2017; See List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signalling by that receptor).Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. More help
Process Object Action
DNA topoisomerase II activity abnormal

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
topoisomerase II binding, infant leukaemia MolecularInitiatingEvent Agnes Aggy (send email) Open for comment. Do not cite EAGMST Under Review

Stressors

This is a structured field used to identify specific agents (generally chemicals) that can trigger the KE. Stressors identified in this field will be linked to the KE in a machine-readable manner, such that, for example, a stressor search would identify this as an event the stressor can trigger. NOTE: intermediate or downstream KEs in one AOP may function as MIEs in other AOPs, meaning that stressor information may be added to the KE description, even if it is a downstream KE in the pathway currently under development.Information concerning the stressors that may trigger an MIE can be defined using a combination of structured and unstructured (free-text) fields. For example, structured fields may be used to indicate specific chemicals for which there is evidence of an interaction relevant to this MIE. By linking the KE description to a structured chemical name, it will be increasingly possible to link the MIE to other sources of chemical data and information, enhancing searchability and inter-operability among different data-sources and knowledgebases. The free-text section “Evidence for perturbation of this MIE by stressor” can be used both to identify the supporting evidence for specific stressors triggering the MIE as well as to define broad chemical categories or other properties that classify the stressors able to trigger the MIE for which specific structured terms may not exist. More help

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected from an ontology. In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help
Term Scientific Term Evidence Link
mammals mammals High NCBI

Life Stages

The structured ontology terms for life-stage are more comprehensive than those for taxa, but may still require further description/development and explanation in the free text section. More help

Sex Applicability

The authors must select from one of the following: Male, female, mixed, asexual, third gender, hermaphrodite, or unspecific. More help
Term Evidence
Mixed High

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. For example, the biological state being measured could be the activity of an enzyme, the expression of a gene or abundance of an mRNA transcript, the concentration of a hormone or protein, neuronal activity, heart rate, etc. The biological compartment may be a particular cell type, tissue, organ, fluid (e.g., plasma, cerebrospinal fluid), etc. The role in the biology could describe the reaction that an enzyme catalyses and the role of that reaction within a given metabolic pathway; the protein that a gene or mRNA transcript codes for and the function of that protein; the function of a hormone in a given target tissue, physiological function of an organ, etc. Careful attention should be taken to avoid reference to other KEs, KERs or AOPs. Only describe this KE as a single isolated measurable event/state. This will ensure that the KE is modular and can be used by other AOPs, thereby facilitating construction of AOP networks. More help

Type II topoisomerases are ubiquitous enzymes that are required for proper chromosome structure and segregation and play important roles in DNA replication, transcription, and recombination. Type II topoisomerases change DNA topology by breaking and rejoining double-stranded DNA. These enzymes can introduce or remove supercoils and can separate two DNA duplexes that are intertwined. Type II topoisomerases relax DNA and remove knots and tangles from the genetic material by passing an intact double helix (transport segment) through a transient double-stranded break that they generate in a separate DNA segment (gate segment). Humans encode two closely related isoforms of the type II enzyme. Topoisomerase II Þ is essential for the survival of proliferating cells and topoisomerase II ß plays critical roles during development. However, because these enzymes generate double-stranded DNA breaks during their crucial catalytic functions, the consequences are not only beneficial. Although essential to cell survival, they also pose an intrinsic threat to genomic integrity every time they act. Beyond their critical physiological functions, topoisomerase IIÞ and IIß are the primary targets for some of the most active and widely prescribed drugs currently used for the treatment of human cancers. These agents kill cells by increasing levels of covalent topoisomerase II-cleaved DNA complexes that are normal, but fleeting, intermediates in the catalytic DNA strand passage reaction. Many chemicals do so by inhibiting the ability of the type II enzymes to ligate cleaved DNAs. When the resulting enzyme-associated DNA breaks are present in sufficient concentrations, they can trigger cell death pathways. Chemicals that target type II enzymes are referred to as topoisomerase II poisons because they convert these indispensable enzymes to potent physiological toxins that generate DNA damage in treated cells. Because the enzyme functions by passing an intact double helix through a transient double-stranded break, any disturbances in its function, e.g. by chemical inhibitors, could have a profound effect on genomic stability, resulting in DNA repair response, gene and chromosomal damage, initiation of apoptosis and ultimate cell death. A double-strand break and error-prone non-homologous end-joining (NHEJ) DNA repair mechanism may lead to gene rearrangements; chromosomal translocations and consequently fusion genes (see Figure 33). A comprehensive description of TopoII enzymes and their functions and derangements could be found in recent review articles (Cowell and Austin 2012; Pendleton et al 2014; Ketron and Osheroff 2014).

Fig.33: TOP2 Poisons, downstream events. TOP2 poisons inhibit the religation step of the TOP2 reaction cycle, leading to accumulation of covalent TOP2-DNA cleavage complexes. These lesions are cytotoxic and lead to activation of the DNA damage response and potentially apoptosis. Alternatively these lesions are repaired, largely through the non-homologous end-joining pathway. Translocations observed in therapy-related leukemia are presumed to occur as a result of mis-repair, joining two heterologous ends. (from Cowell and Austin 2012)

DNA topoisomerase (Top) II enzyme “poisons” disturb the normal TopoII enzyme function and cause a ‘hanging double strand break (DSB)’ at a specified DNA sequence. The above description of the MIE is of significance because there are 3 different kinds of “poisons" of TopoII enzyme, out of which competitive inhibitors prevent the function of the enzyme and cause cell death, whereas other interfacial and covalent inhibitors may cause – depending on the situation – other consequences of DNA damage response including chromosomal rearrangements (Pendleton et L 2014; Lu et al 2015). A further prerequisite for the specific outcome, i.e. creation of chromosomal rearrangement, is that TopoII “poison” has to occur in an especially vulnerable and correct hot spot in the MLL locus in the right target cell vulnerable to transformation.

The MIE, topo II poisons, can occur prenatally i.e. prenatal exposure to topo II poisons. Human embryonic stem cells are more sensitive to topo II inhibition than postnatal CD34+ cells, linking embryonic exposure to topoisomerase II poisons to genomic instability. However, little is know about the nature of the target cell for transformation (Bueno et al. 2011).

How It Is Measured or Detected

One of the primary considerations in evaluating AOPs is the relevance and reliability of the methods with which the KEs can be measured. The aim of this section of the KE description is not to provide detailed protocols, but rather to capture, in a sentence or two, per method, the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements. Methods that can be used to detect or measure the biological state represented in the KE should be briefly described and/or cited. These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA).Key considerations regarding scientific confidence in the measurement approach include whether the assay is fit for purpose, whether it provides a direct or indirect measure of the biological state in question, whether it is repeatable and reproducible, and the extent to which it is accepted in the scientific and/or regulatory community. Information can be obtained from the OECD Test Guidelines website and the EURL ECVAM Database Service on Alternative Methods to Animal Experimentation (DB-ALM). ?

The identification and measurement of the inhibition of TopoII enzymes is made more difficult by the presence of different molecular mechanisms (see above). However, some assays are used in pharmacological research to screen TopoII “poisons”, including cell-free decatenation assay (Schroeter et al., 2015). The most important mode, the cleavage activity of TopoII can be studied in vitro, by using a human recombinant enzyme and an appropriate double-stranded plasmid as a target to quantitate double-strand breaks (Fortune and Osheroff 1998). A cleavage can also be indirectly detected by measuring various indicators of DNA damage response, such as ATM activity, p53 expression, γH2AX or Comet assay (Li et al 2014, Schroeter et al., 2015, Castano et al 2016).

It is useful to note that several chemicals identified as TopoII “poisons”do require metabolic oxidation to become active inhibitors. Etoposide itself is converted via the catechol metabolite to etoposide 3-quinone, which is a covalent TopoII poison (Smith et al 2014), whereas etoposide and its catechol are interfacial inhibitors. Curcumin is also an active TopoII poison due to its oxidized metabolites (Gordon et al 2015). This fact deserves consideration if a screening for TopoII inhibition is envisaged.

Topoisomerase poisons stabilize the covalent enzyme–DNA complex. There are several key characteristics of this complex: it includes protein covalently bound to DNA as well as a strand break in the DNA substrate, and it is also freely reversible. Accordingly, if the chemical is removed the enzyme rapidly reseals the DNA. Covalent complexes are quantified in two ways: by measuring the levels of protein covalently bound to DNA or by directly assaying for DNA strand breaks in the presence of topoisomerase and test agent or known drug. The assay directly measures DNA strand breaks induced by topoisomerase I in a substrate that carries a strong DNA cleavage site. Similarly, the plasmid linearization assay measures double strand breaks induced in plasmid DNA by topoisomerase II. The Alternate Protocol allows for the visualization of breaks induced on a larger substrate. Different protocols are used to measure the amount of the cleavage complex by determining the levels of topoisomerases that are covalently associated with DNA. Since the covalent complex is a normal step in the topoisomerase reaction, it can be detected (using very sensitive assays) even in the absence of a topoisomerase poison. However, addition of a topoisomerase poison greatly increases the levels of covalent comple. Protocol and procedure details for mewasuring topoisomerase inhibition are fully reported in Nitiss et al. 2012.

In vivo complex enzyme assay (Rodriguez et al. 2020): hESCs were either immediately lysed in 1 % (w/v) sarkosyl (Sigma L7414). Lysates were processed according to the in vivo complex of enzyme (ICE) assay (Nitiss, Soans, Rogojina, Seth, & Mishina, 2012; Schellenberg et al., 2017). Briefly, sheared samples were centrifuged with a CsCl (Applichem-Panreac, A1098) gradient at 57,000 r.p.m. for 20 h at 25 °C using 3.3 ml 13 x 33 mm polyallomer Optiseal tubes (Beckman Coulter) in a TLN100 rotor (Beckman Coulter). For slot blotting, ICE samples containing 1, 2 or 4 µg of DNA were transferred onto Odyssey Nitrocellulose Membranes (LI-COR Biosciences) using a Bio-Dot SF Microfiltration Apparatus (Biorad). For western blot of ICE, samples were resuspended in 12,000 units of Micrococcal Nuclease (MNase, NEB 0247S), 1 x MNase buffer (NEB, B0247S) and 100 µg / mL BSA (NEB, B9000S), then incubated at 37 °C for 6 h. Samples were run in 10% SDS-PAGE and transferred to Immobilon-FL Transfer Membranes (Millipore). Membranes were blocked for 1 h in Odyssey Blocking Buffer (LI-COR Biosciences), then incubated for 2 h with primary antibodies in the same buffer with additional 0.1% (v/v) TWEEN 20, washed 3x with TBS-0.1%-TWEEN20, incubated with secondary antibodies for 1 h, and finally washed again. Once the membranes were dry, slots were analyzed and quantified in Odyssey CLx using ImageStudio Odyssey CLx Software.

Domain of Applicability

This free text section should be used to elaborate on the scientific basis for the indicated domains of applicability and the WoE calls (if provided). While structured terms may be selected to define the taxonomic, life stage and sex applicability (see structured applicability terms, above) of the KE, the structured terms may not adequately reflect or capture the overall biological applicability domain (particularly with regard to taxa). Likewise, the structured terms do not provide an explanation or rationale for the selection. The free-text section on evidence for taxonomic, life stage, and sex applicability can be used to elaborate on why the specific structured terms were selected, and provide supporting references and background information.  More help

DNA topoisomerases are ubiquitous enzymes, which control the integrity of double-stranded DNA. They are thus key enzymes at all levels of living organisms. The available evidence suggest that important differences in sensitivity to topoisomerase inhibition  might exist among different cell types, depending on the amount of proliferative burden, of the TopoII enzymes and on physiological repair processes. Mesodermal precursor or hematopoietic stem and progenitor cells (HSPCs) are rapidly dividing cells with a high content of TopoII and for these reasons they can be a sensitive target during a critical developmental window (Hernandez and Menendez 2016).  In addition, evidence from micronuclei assay studies conducted in untreated and chemical-treated foetuses and newborns show that both the baseline and chemically induced micronuclei frequencies are higher in the foetuses and infants than in adults (Udroiu et al 2016). This is possibly indicating a greater sensitivity to genotoxic insult during development which can be due to the higher proliferation rate and lower ability of DNA repair of the hematopoietic stem cells. However, the role that the different microenvironments (foetal liver, infant bone marrow and adult bone marrow) during ontogenesis can exert on cell sensitivity cannot be ruled out (Udroiu et al. 2016). The existence of relevant interspecies differences is unknown, but it cannot be ruled out presently.

Evidence for Perturbation by Stressor

Overview for Molecular Initiating Event

When a specific MIE can be defined (i.e., the molecular target and nature of interaction is known), in addition to describing the biological state associated with the MIE, how it can be measured, and its taxonomic, life stage, and sex applicability, it is useful to list stressors known to trigger the MIE and provide evidence supporting that initiation. This will often be a list of prototypical compounds demonstrated to interact with the target molecule in the manner detailed in the MIE description to initiate a given pathway (e.g., 2,3,7,8-TCDD as a prototypical AhR agonist; 17α-ethynyl estradiol as a prototypical ER agonist). Depending on the information available, this could also refer to chemical categories (i.e., groups of chemicals with defined structural features known to trigger the MIE). Known stressors should be included in the MIE description, but it is not expected to include a comprehensive list. Rather initially, stressors identified will be exemplary and the stressor list will be expanded over time. For more information on MIE, please see pages 32-33 in the User Handbook.

Etoposide is one of the most well studied topoisomerase II targeted agents. It stabilizes covalent topoisomerase II-cleaved DNA complexes (ie cleavage complexes) by interacting at the enzyme-DNA interface in a noncovalent manner (Smith et al. 2014).

Etoposide ( and its derivatives) stimulate DNA cleavage mediated by yeast topoisomerase II.  As a result of etoposide action, high levels of topoisomerase II-associated DNA breaks accumulate in treated cells (Hande et al. 1998; Ross et al 1984; Wistelrman et al.2007).

Etoposide quinone induces DNA cleavage via an enzyme-mediated mechanism. Control reactions were conducted in the absence of enzyme or drug (DNA Control), in the presence of 30 μM etoposide quinone without enzyme (+EQ −hTIIβ), or in the presence of topoisomerase IIβ without drug (−EQ +hTIIβ). The quinone induced ∼4 times more enzyme-mediated DNA cleavage than did the parent drug. Furthermore, the potency of etoposide quinone was ∼2 times greater against topoisomerase IIβ than it was against topoisomerase IIα, and the drug reacted ∼2–4 times faster with the β isoform. Etoposide quinone induced a higher ratio of double- to single-stranded breaks than etoposide, and its activity was less dependent on ATP (Smith et al. 2014).

TOP2 isoforms covalently bound to genomic DNA in  hESC after 15 min treatment with etoposide 1-100uM (Rodriguez et al.2020).

 

 

Etoposide

Etoposide is one of the most well studied topoisomerase II-targeted agents in clinical use. The drug stabilizes covalent topoisomerase II-cleaved DNA complexes (i.e., cleavage complexes) by interacting at the enzyme–DNA interface in a noncovalent manner. Once the double helix is cut, the drug slips (i.e., intercalates) between the 3′-hydroxyl and the enzyme-linked 5′-phosphate at the cleaved scissile bond and acts as a physical block to topoisomerase II-mediated DNA ligation. Etoposide and other drugs that utilize this mechanism are termed “interfacial topoisomerase II poisons”. The catechol displayed properties that were similar to those of the parent drug and appeared to be an interfacial poison. The properties of the quinone metabolite differed from those of etoposide, and the quinone appeared to function by a different mechanism. Previous studies with quinones and other protein-reactive agents have found that some of these compounds increase levels of topoisomerase II-mediated DNA cleavage by covalently adducting to the enzyme at residues that are distal to the active site.Thus, these agents are termed “covalent topoisomerase II poisons”. It is believed that covalent poisons enhance DNA cleavage, at least in part, by closing the N-terminal gate of the protein. Several lines of evidence suggest that etoposide quinone poisons topoisomerase II by this latter, covalent mechanism (Smith NA, 2014).

etoposide quinone

Etoposide metabolites, ie etoposide quinone, is also a potent topoisomerase IIß poisons. The quinone is able to induce about 4 times more enzyme-mediated DNA clevage than does the parent drug. Furthermore, the potency of etoposide quinone was about 2 times greater against topoisomerase IIß than it is agains topoisomerase IIÞ, and it reacts about 2 to 4 time faster with the ß isoform. The quinone metabolite induces a higher ratio of double - to single strand breaks than the parent chemical, and its activity is less dependent on ATP. Whereas etoposide acts as an interfacial topoisomerase II poison, etoposide quinone displayed all of the hallmarks of a covalent poison: the activity of the metabolite was abolished by reducing agents, and the compound inactivated topoisomerase IIβ when it was incubated with the enzyme prior to the addition of DNA​ (Smith et al. 2014)

References

List of the literature that was cited for this KE description. Ideally, the list of references, should conform, to the extent possible, with the OECD Style Guide (https://www.oecd.org/about/publishing/OECD-Style-Guide-Third-Edition.pdf) (OECD, 2015). More help

Alexander FE, Patheal SL, Biondi A, Brandalise S, Cabrera ME, Chan LC, Chen Z, Cimino G, Cordoba JC, Gu LJ, Hussein H, Ishii E, Kamel AM, Labra S, Magalhaes IQ, Mizutani S, Petridou E, de Oliveira MP, Yuen P, Wiemels JL, Greaves MF. Transplacental chemical exposure and risk of infant leukemia with MLL gene fusion. Cancer Res. 2001 Mar 15;61(6):2542-6.

Hande KR. Etoposide: four decades of development of a topoisomerase II inhibitor. Eur. J. Cancer. 1998;34:1514–1521.

Azarova AM, Lin RK, Tsai YC, Liu LF, Lin CP, Lyu YL. Genistein induces topoisomerase IIbeta- and proteasome-mediated DNA sequence rearrangements: Implications in infant leukemia. Biochem Biophys Res Commun. 2010 Aug 13;399(1):66-71. doi: 10.1016/j.bbrc.2010.07.043.

Bandele OJ, Osheroff N. Bioflavonoids as poisons of human topoisomerase II alpha and II beta. Biochemistry. 2007 May 22;46(20):6097-108.

Barjesteh van Waalwijk van Doorn-Khosrovani S, Janssen J, Maas LM, Godschalk RW, Nijhuis JG, van Schooten FJ. Dietary flavonoids induce MLL translocations in primary human CD34+ cells. Carcinogenesis. 2007 Aug;28(8):1703-9.

Castaño J, Herrero AB, Bursen A, González F, Marschalek R, Gutiérrez NC, Menendez P.Expression of MLL.AF4 or 1 AF4.MLL fusions 2 does not impact the efficiency of DNA damage repair. Nucl Acid Res 2016; in press

Cowell IG, Austin CA. Mechanism of generation of therapy related leukemia in response to anti-topoisomerase II agents. Int J Environ Res Public Health. 2012 Jun;9(6):2075-91. doi: 10.3390/ijerph9062075.

Fortune JM, Osheroff  N. Merbarone inhibits the catalytic activity of human topoisomerase IIalpha by blocking DNA cleavage. J Biol Chem. 1998; 273(28): 17643-17650.

Gordon ON, Luis PB, Ashley RE, Osheroff N, Schneider C. Oxidative Transformation of Demethoxy- and Bisdemethoxycurcumin: Products, Mechanism of Formation, and Poisoning of Human Topoisomerase IIβ. Chem Res Toxicol. 2015; 28(5): 989-996. doi: 10.1021/acs.chemrestox.5b00009.

Hernandez Jerez A and Menendez P. Linking pesticide exposure with pediatric leukemia: potential underlying mechanisms. Int J Mol Sci 2016; 17: 461.

Lanoue L, Green KK, Kwik-Uribe C, Keen CL. Dietary factors and the risk for acute infant leukemia: evaluating the effects of cocoa-derived flavanols on DNA topoisomerase activity. Exp Biol Med (Maywood). 2010; 235(1): 77-89. doi: 10.1258/ebm.2009.009184.

Li Z, Sun B, Clewell RA, Adeleye Y, Andersen ME, Zhang Q. Dose-response modeling of etoposide-induced DNA damage response. Toxicol Sci. 2014 Feb;137(2):371-84. doi: 10.1093/toxsci/kft259.

Lopez-Lazaro M, Willmore E, Austin CA. The dietary flavonoids myricetin and fisetin act as dual inhibitors of DNA topoisomerases I and II in cells. Mutat Res. 2010 Feb;696(1):41-7. doi: 10.1016/j.mrgentox.2009.12.010.

Lu C, Liu X, Liu C, Wang J, Li C, Liu Q, Li Y, Li S, Sun S, Yan J, Shao J. Chlorpyrifos Induces MLL Translocations Through Caspase 3-Dependent Genomic Instability and Topoisomerase II Inhibition in Human Fetal Liver Hematopoietic Stem Cells. Toxicol Sci. 2015; 147(2): 588-606. doi: 10.1093/toxsci/kfv153.

Nitiss JLSoans ERogojina ASeth AMishina M. 2012, Topoisomerase assays.Curr Protoc Pharmacol. 2012 Jun;Chapter 3:Unit 3.3.. doi: 10.1002/0471141755.ph0303s57.

Pendleton M, Lindsey RH Jr, Felix CA, Grimwade D, Osheroff N. Topoisomerase II and leukemia. Ann N Y Acad Sci. 2014 Mar;1310:98-110. doi: 10.1111/nyas.12358.

Rodríguez‐Cortez, V C, Menéndez, P, 2020. Genotoxicity of permethrin and clorpyriphos on human stem and progenitor cells at different ontogeny stages: implications in leukaemia development. EFSA supporting publication 2020: 17( 5): EN‐1866. 35 pp. doi: 10.2903/sp.efsa.2020.EN‐1866

Ross JA, Potter JD, Reaman GH, Pendergrass TW, Robison LL. Maternal exposure to potential inhibitors of DNA topoisomerase II and infant leukemia (United States): a report from the Children's Cancer Group. Cancer Causes Control. 1996 Nov;7(6):581-590.

Ross W, Rowe T, Glisson B, Yalowich J, Liu L. Role of topoisomerase II in mediating epipodophyllotoxin-induced DNA cleavage. Cancer Res. 1984;44:5857–5860.

Sanjuan-Pla A, Bueno C, Prieto C, Acha P, Stam RW, Marschalek R, Menendez P. Revisiting the biology of infant t(4;11)/MLL-AF4+ B-cell acute lymphoblastic leukemia. Blood. 2015; 126(25): 2676-2685 DOI 10.1182/blood-2015-09-667378.

Schellenberg, M. J., Lieberman, J. A., Herrero‐Ruiz, A., Butler, L. R., Williams, J. G. and Muñoz‐Cabello, A. M. Williams, R. S. (2017). ZATT (ZNF451)‐mediated resolution of topoisomerase 2 DNA‐protein cross‐links. Science, 357(6358), 1412–1416. https://doi.org/10.1126/science.aam6468

Schroeter A, Groh IA, Favero GD, Pignitter M, Schueller K, Somoza V, Marko D. Inhibition of topoisomerase II by phase II metabolites of resveratrol in human colon cancer cells. Mol Nutr Food Res. 2015 Oct 12. doi: 10.1002/mnfr.201500352.

Smith NA, Byl JA, Mercer SL, Deweese JE, Osheroff N. Etoposide quinone is a covalent poison of human topoisomerase IIβ. Biochemistry. 2014; 53(19): 3229-3236. doi: 10.1021/bi500421q.

Spector LG, Xie Y, Robison LL, Heerema NA, Hilden JM, Lange B, Felix CA, Davies SM, Slavin J, Potter JD, Blair CK, Reaman GH, Ross JA. Maternal diet and infant leukemia: the DNA topoisomerase II inhibitor hypothesis: a report from the children's oncology group. Cancer Epidemiol Biomarkers Prev. 2005 Mar;14(3):651-655.

Strick R, Strissel PL, Borgers S, Smith SL, Rowley JD. Dietary bioflavonoids induce cleavage in the MLL gene and may contribute to infant leukemia. Proc Natl Acad Sci U S A. 2000 Apr 25;97(9):4790-5.

Udroiu I., Sgura A. Genotoxicity sensitivity of the developing hematopoietic system. 2012. Mutation Research 2012; 767: 1-7.

Wilstermann A. M.; Bender R. P.; Godfrey M.; Choi S.; Anklin C.; Berkowitz D. B.; Osheroff N.; Graves D. E. (2007) Topoisomerase II-drug interaction domains: Identification of substituents on etoposide that interact with the enzyme. Biochemistry 46, 8217–8225.