Modeling low-dose radiation-induced acute myeloid leukemia in male CBA/H mice

Sjors Stouten,Rosemary Finnon,Christophe Badie,Sjoerd Verduyn Lunel,Fieke Dekkers

doi:10.1007/s00411-020-00880-9

Abstract

The effect of low-dose ionizing radiation exposure on leukemia incidence remains poorly understood. Possible dose-response curves for various forms of leukemia are largely based on cohorts of atomic bomb survivors. Animal studies can contribute to an improved understanding of radiation-induced acute myeloid leukemia (rAML) in humans. In male CBA/H mice, incidence of rAML can be described by a two-hit model involving a radiation-induced deletion with Sfpi1 gene copy loss and a point mutation in the remaining Sfpi1 allele. In the present study (historical) mouse data were used and these processes were translated into a mathematical model to study photon-induced low-dose AML incidence in male CBA/H mice following acute exposure. Numerical model solutions for low-dose rAML incidence and diagnosis times could respectively be approximated with a model linear-quadratic in radiation dose and a normal cumulative distribution function. Interestingly, the low-dose incidence was found to be proportional to the modeled number of cells carrying the Sfpi1 deletion present per mouse following exposure. After making only model-derived high-dose rAML estimates available to extrapolate from, the linear-quadratic model could be used to approximate low-dose rAML incidence calculated with our mouse model. The accuracy in estimating low-dose rAML incidence when extrapolating from a linear model using a low-dose effectiveness factor was found to depend on whether a data transformation was used in the curve fitting procedure.

Highlights

Many epidemiological studies have been conducted to elucidate the relationship between low-dose (LD) ionizing radiation (IR) exposure and leukemia incidence (Hsu et al 2013; Preston et al 1994; Pearce et al 2012; Laurier et al 2017)
Loss of clonal potential of hematopoietic stem cells (HSCs) target cells was described through the LQ model (Fig. 2a), yielding model predictions that are in line with gamma-irradiated Slam-HSC (LSK, Flk2, CD150+, CD48-) survival data (Mohrin et al 2010) not included in the fitting procedure
The model was extended by explicitly including cell survival and del2 induction in terms of the LQ model and by coupling bone marrow leukemogenesis to a survival model in which mice can die from other causes than radiation-induced acute myeloid leukemia (rAML)

Summary

Introduction

Many epidemiological studies have been conducted to elucidate the relationship between low-dose (LD) ionizing radiation (IR) exposure and leukemia incidence (Hsu et al 2013; Preston et al 1994; Pearce et al 2012; Laurier et al 2017). Data analyses of the Japanese atomic bomb survivors life-span study showed that both a linear-quadratic (LQ) and a preferred purely quadratic model can describe acute myeloid leukemia (AML) risk over a wide dose range (Preston et al 1994; Richardson et al 2009; Hsu et al 2013). The dose and dose-rate effectiveness factor (DDREF) has been introduced by the International Commission on Radiological Protection (ICRP) to account for possible overestimation of risk, when extrapolating from HD (rate) data to infer cancer risk possibly observed after LD (rate) exposure (ICRP 1991).

Methods

Results

Conclusion