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Event: 1254

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

Infant leukaemia

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
IFL

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

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

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 AdverseOutcome Andrea Terron (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
Name
Etoposide

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
Life stage Evidence
Birth to < 1 month High

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

B cell Acute Lymphocytic Leukaemia (ALL) is the most frequent cancer in children. Infant leukaemia is a rare haematological disease with an incidence of 1 in 106 newborns, accounting for 10% of all B cell-ALLs in children younger than 15 years, manifesting soon after birth (<1 year) and displaying an intermediate prognosis except for some cytogenetic subgroups such as MLL -rearranged (MLL-r) B cell-ALL, which remains an outlier high-risk group having a poor prognosis (Sanjuan-Pla et al., 2015). Compared with the more frequent childhood leukaemias, infant leukaemia shows distinct features:

- An early neonatal manifestation suggests an in utero initiation as an ‘intrauterine developmental disease’ (Greaves, 2015; Sanjuan-Pla et al., 2015);

- Rearrangements of the MLL gene on the q23 band of chromosome 11 as the hallmark genetic abnormality (Joannides and Grimwade, 2010).

- However, MLL is not the only translocation gene. Whereas about 60–80% of infant ALL carry an MLL(Sam et al., 2012; Jansen et al., 2007), for infant acute myeloid leukaemia (AML) the percentage of MLL is lower than 40%;

- The MLL-r occurs at an early stage of development, with the target cells (still unidentified) being likely theHSPCs in foetal liver and/or pre-haematopoietic mesodermal foetal precursors (Bueno et al., 2009; Menendez et al., 2009);

- Infant MLL-r leukaemia has the least number of somatic mutations among all the sequenced cancers (1.3 vs 6.5/case; Andersson et al., 2015; Dobbins et al., 2013), pointing to the lack of a “second hit” assumed in the classic carcinogenesis paradigm.

The overall scientific evidence, including the stable genome of patients, suggests that infant leukaemia originates from one “big-hit” occurring during a critical developmental window of HSPC vulnerability (Andersson et al., 2013; Greaves, 2015). In contrast to the “two-hit” model of the adult and childhood leukaemias, infant leukaemia is a developmental disorder where the differentiation arrest and clonal expansion are a direct consequence of in utero MLL translocation in target HSPCs. Even if MLL is not present in 100% of infant leukaemias, the ‘MLL rearranged (MLL-r) infant leukaemia’, especially MLL-r B-ALL, is taken here as a model for the disease principally because of the quantity of scientific evidence.

Clinically,IFL is characterised by symptoms of leukaemia – thrombocytopenia resulting in sensitivity to bruising and bleeding, anaemia with pallor and fatigue, neutropenia associated with increased susceptibility to infections – are principally due to the displacement of the normal haematopoiesis by expansion of leukaemia cells. Leukemic infiltration of the brain is common at diagnosis of the infant leukaemia (Hunger and Mulligham, 2015).

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). ?

Haematological methods – identification of leukaemia cells and routine blood cell counts; observations of clinical symptoms.

Following clinical diagnosis, methods for refined diagnosis include bone marrow aspirates for immunophenotypic analyses and cytogenetic assays for molecular stratification.

The carcinogenicity assays and the extended one generation test (OECD 443) include endpoints that can potentially explore the AO; however, considerations should be made on the specificity of the disease to humans. Indeed, IFL, as such, is not an animal disease and never reported as chemically induced outcome in cancerogenesis studies. it should however be noted that cancerogenesis studis are generally performed in young adult animals and protocol including the treatment of the dams  from the mating period are not common. for this reason, the sensitivity of the cancerogenesis study to capture this hazard is at its best unknown.

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

Infant leukaemia is a paediatric leukaemia likely resulting from gene-environmental interactions. The limited data available suggest that dietary and environmental exposure to substances targeting topoisomerases together with reduced ability of the foetus or their mother to detoxify such compounds because of the polymorphic variants of given genes could contribute to the development of this AO (Hernadez  et al. 2016).

In animals the disease is not known and artificial animal models able to reproduce the disease have limitations. Bardini et al (2015) has however developed a xenograft mouse model with patient MLL-AF4-involving leukoblasts transplanted. 

Evidence for Perturbation by Stressor

Etoposide

Topo II is a well validated anti-cancer target and Topo II poisons are widely used and effective therapeutic agents; but they are associated with the occurence of late complications, including therapy-related acute leukaemia (Cowell and Austin, 2012). Secondary acute leukaemia carrying MLL-r is an adverse effect observed in patients treated with etoposide and a few other anticancer agents. Characteristics of the disease are in many ways analogous to those in infant leukaemia (Joannides et al., 2010, 2011). MLL rearrangement, short latency and poor prognosis, strongly suggest that infant leukaemia and treatment-related leukaemia are sufficiently similar to allow for inferences to be made regarding tentative aetiological factors, molecular events and disease progression and manifestation.

Regulatory Significance of the Adverse Outcome

An AO is a specialised KE that represents the end (an adverse outcome of regulatory significance) of an AOP. For KEs that are designated as an AO, one additional field of information (regulatory significance of the AO) should be completed, to the extent feasible. If the KE is being described is not an AO, simply indicate “not an AO” in this section.A key criterion for defining an AO is its relevance for regulatory decision-making (i.e., it corresponds to an accepted protection goal or common apical endpoint in an established regulatory guideline study). For example, in humans this may constitute increased risk of disease-related pathology in a particular organ or organ system in an individual or in either the entire or a specified subset of the population. In wildlife, this will most often be an outcome of demographic significance that has meaning in terms of estimates of population sustainability. Given this consideration, in addition to describing the biological state associated with the AO, how it can be measured, and its taxonomic, life stage, and sex applicability, it is useful to describe regulatory examples using this AO. More help

Genotoxicity in general and carcinogenicity are apical endpoints in established regulatory guideline studies. TopoII poisoning has been listed as one of the potential mechanisms of genotoxicity and carcinogenicity in the ICH M7 guideline for human medicines. It is also known that some manifestations of genotoxicity in tests measuring chromosomal aberrations, micronuclei or DNA and chromosome damage (Comet assay) are partially due to double-strand breaks created by the disturbed action of TopoII enzymes.

 The extended one generation test (OECD 443) includes a developmental immunotoxicity cohort. At present the cohort may identify post-natal effects of prenatal and neonatal exposures on the immune tissues and white blood cells population. However, each regulatory guideline study has potential limitations e.g. no specific parameters are in place to identify a pattern relevant to infant leukemia in humans in the extended one generation test, no treatment is occurring during the early in-utero development phase in the carcinogenicity assay and no considerations on the possible higher sensitivity of the HSC are in place for the genotoxicity assays.

Epidemiological evidence  linking pesticide exposure to infant leukaemia, also suggests that pesticide exposure may have a greater impact on children than adults; though, almost all of the available evidence does  not make a distinction between infant and childhood leukaemia.   However, most epidemiological studies are limited because no specific pesticides have been directly associated with the risk of leukaemia, but rather the broad term “pesticide exposure” (Hernandez and Menendez 2016). In this perspective, this AOP would provide a regulatory relevant support for understanding the potential of a chemical to be involved in this toxicological pathway.

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

Bardini M, Woll PS, Corral L, Luc S, Wittmann L, Ma Z, Lo Nigro L, Basso G, Biondi A, Cazzaniga G, Jacobsen SE. Clonal variegation and dynamic competition of leukemia-initiating cells in infant acute lymphoblastic leukemia with MLL rearrangement. Leukemia. 2015 Jan;29(1):38-50. doi: 10.1038/leu.2014.154.

Bueno C, Catalina P, Melen GJ, Montes R, Sanchez L, Ligero G, Garcia-Perez JL, Menendez P. Etoposide induces MLL rearrangements and other chromosomal abnormalities in human embryonic stem cells. Carcinogenesis 2009; 30(9): 1628-1637. doi: 10.1093/carcin/bgp169.

Ezoe S. Secondary leukemia associated with the anti-cancer agent, etoposide, a topoisomerase II inhibitor. Int J Environ Res Public Health. 2012 Jul;9(7):2444-53. doi: 10.3390/ijerph9072444.

Gole B, Wiesmüller L. Leukemogenic rearrangements at the mixed lineage leukemia gene (MLL)-multiple rather than a single mechanism. Front Cell Dev Biol. 2015 Jun 25;3:41. doi: 10.3389/fcell.2015.00041.

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

Hunger SP, Mullighan CG. Acute Lymphoblastic Leukemia in Children. N Engl J Med 2015; 73: 1541-1552.

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. 

Moneypenny CG, Shao J, Song Y, Gallagher EP. MLL rearrangements are induced by low doses of etoposide in human fetal hematopoietic stem cells. Carcinogenesis. 2006; 27(4):874–81. Epub 2005/12/27. doi: 10.1093/carcin/bgi322

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.