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Event: 1254

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Infant leukaemia

Short name
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IFL
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Biological Context

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Level of Biological Organization
Individual

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling).  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 signaling 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.  Further information on Event Components and Biological Context may be viewed on the attached pdf. 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 Do not cite WPHA/WNT Endorsed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 KE.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

An indication of the the relevant life stage(s) for this KE. More help
Life stage Evidence
Birth to < 1 month High

Sex Applicability

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Term Evidence
Mixed High

Key Event Description

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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

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.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). Do not provide detailed protocols. More help

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 TG 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. Regarding the cancerogenesis studies, it should however be noted that they 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

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided).  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. 

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. 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 studies 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. It is however worth noting that IFL is not an animal disease  and therefore the outcome of a chemically induced MLL translocation can likely only be tested at KE levels. In addition, MLL translocation is clearly a common node to alternative AOs not described in this AOP (chemotherapy induced leukaemia) and genotoxicity per se should be considered as adverse.

References

List of the literature that was cited for this KE description. 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.