3.4. Investigations of the occurrence of leukaemia in suitable animal models

Project management: Fraunhofer ITEM, Hannover
Start: 1 August 2020
End: 31 July 2023

Background

The most common type of leukaemia in children is acute lymphoblastic leukaemia, which most often originates from precursor B cells (preB-ALL). PreB-ALL is characterised by the occurrence of recurrent chromosomal translocations (e.g. the ETV6-RUNX translocation). These changes appear to be the "first hit" for a normal haematopoietic progenitor or stem cell to transform into a pre-leukaemic cell; however, they are not sufficient for leukaemia to develop. Secondary mutations, which could arise either spontaneously or through environmental effects, are necessary for this. Based on consistent results of epidemiological studies, low-frequency magnetic fields are discussed as a possible environmental factor that can lead to an increased risk for childhood leukaemia. However, the epidemiological results have not yet been confirmed by animal experiments and cell studies. To further clarify a possible link between ELF-MF and childhood leukaemia , the EU-funded project “Advanced Research on Interaction Mechanisms of electromagnetic exposures with Organisms for Risk Assessment” (ARIMMORA) was started in 2011 ^[1]. One aim of the ARIMMORA project was to investigate the role of extremely low frequency magnetic fields (ELF-MF) in a transgenic pre-B-ALL mouse model. For this purpose, the Sca-1-ETV6-RUNX1 mouse model was used; in this model, the most common translocation in childhood leukaemia, the ETV6-RUNX1 translocation, is constitutively expressed in hematopoietic stem/progenitor cells ^[2]. In an initial experiment, Sca1-ETV6-RUNX1 mice were exposed to 1.5 mT ELF-MF starting in utero up to an age of 3 months and then observed for the development of leukaemia up to an age of 2 years. One out of the 30 exposed mice and none of the 65 non-exposed mice developed preB-ALL. However, because of the small group size, the result was not statistically significant.

Objectives

The results from the ARIMMORA project are to be reviewed. In order to obtain statistically meaningful results, a larger number of mice will be exposed to ELF-MF, and the health status of the animals will be documented over a period of two years. The same mouse model and exposure conditions as in the ARIMMORA project will be used.

Implementation

For the project, 204 Sca1-ETV6-RUNX1 mice will be exposed to 1.5 mT ELF MF, and 204 mice will be exposed to 0 mT ELF-MF (sham-exposed control group). The animals will be exposed in a blinded manner in two externally indistinguishable exposure facilities. The animals will be exposed 20 h per day starting in utero up to an age of 3 months. After the three-month exposure, the mice will be observed for the development of leukaemia up to an age of 2 years. For this purpose, the mice will remain in the same room under specific pathogen-free conditions. The blinding will be further maintained. A possible development of leukaemia in the animals will be regularly checked by means of blood controls, among other things. The health status of the animals will be regularly checked by measuring body weight and recording clinical symptoms. After the two-year observation phase, the animals will be examined macroscopically and histologically. In addition, haematological tests will be carried out, and the immune status will be checked. Possible neoplastic changes can thus be detected.

References

[1] Schüz, J., et al., Extremely low-frequency magnetic fields and risk of childhood leukemia: A risk assessment by the ARIMMORA consortium. Bioelectromagnetics, 2016. 37(3): p. 183-189.
[2] Campos-Sanchez, E., et al., Novel ETV6-RUNX1 Mouse Model to Study the Role of ELF-MF in Childhood B-Acute Lymphoblastic Leukemia: a Pilot Study. Bioelectromagnetics, 2019. 40(5): p. 343-353.