API

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Relationship: 1635

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

DSB leads to MLL translocation

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
DSB
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help
MLL translocation

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
Inhibitor binding to topoisomerase II leading to infant leukaemia adjacent High Not Specified Agnes Aggy (send email) Open for comment. Do not cite WPHA/WNT Endorsed

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Mixed High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

There is evidence that the inappropriate joining of ‘hanging ends’ following DSB happens in the same transcriptional factory (hub), and the result is a fusion gene and ultimately protein product (Cowell & Austin 2012; Pendleton et al 2014; Sanjuan-Pla et al 2015). The first part of this description has not been shown in the putative target cell, which is still not unequivocally identified, but for the second part there is ample evidence of formation of MLL-AF4 fusion product that has been a result of a very early chromosomal translocation and rejoining. It is of interest that the simultaneously induced specific DSBs in the MLL gene and two different translocation partners (AF4 and AF9) by engineered nucleases in human HSPCs resulted in specific ‘patient-like’ chromosomal translocations (Breese et al 2016).

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Map 2.0

ID Experimental Design Species Upstream Observation Downstream Observation Citation (first author, year) Notes

Evidence Map

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help
Title First Author
Biological Plausibility
Dose Concordance
Temporal Concordance
Incidence Concordance
Biological Plausibility
Dose Concordance Evidence
Temporal Concordance Evidence
Incidence Concordance Evidence
Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

A target cell, i.e. leukaemia-initiating cell, has not been identified with sufficient confidence and consequently there is no target cell model to recapitulate the linkage between TopoII inhibition (‘poisoning’) and the production of DSB in an appropriate target. Recently, by the expression of engineered nucleases (TALENs) to induce simultaneous patient specific double strand breaks in the MLL gene and two different known translocation partners (AF4 and AF9), Breese et al (2015) were able to produce specific chromosomal translocations in K562 cells and in primary HSPCs.

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

Seminal studies demonstrated an in utero, pre-natal origin of these MLLr in monozygotic twins with concordant B-ALL, in retrospective analysis in Guthrie cards and cord bloods (Ford et al., 1993; Gale et al., 1997). A single-pulse of etoposide induces DSBs measured by g-H2AX staining in all primary cell types tested (hESC, fetal-, neonatal- and adult-derived CD34+ HSPCs)(Rodriguez et al. 2020).