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

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

doi:10.1007/s00411-020-00880-9

Cited by 9 publications

(33 citation statements)

References 51 publications

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“…The redeveloped rAML model presented here including an HRS extension is based on previous modeling work (Dekkers et al 2011;Stouten et al 2021) in which, similar to the two-stage models for cancer risk assessment, malignant cells are formed due to the occurrence of two mutations (Moolgavkar et al 1988;Dewanji et al 1989;Leenhouts and Chadwick 1994). Figure 1 shows an overview of the model utilized to quantify the rAML incidence.…”

Section: Background Of the Modelmentioning

confidence: 99%

“…Cells I proliferate and they transform into malignant cells when the codon R235 point mutation occurs in the remaining Sfpi1 allele. The formation of the first malignant cell leads to rAML onset over the course of t lag months, provided that the mouse does not die during that time (Dekkers et al 2011;Stouten et al 2021). The expressions along the arrows correspond with the rates (except for latency t lag ) used in the differential equation model to describe the response of bone marrow cells (N, I and M) to ionizing radiation exposure.…”

Section: Background Of the Modelmentioning

confidence: 99%

“…Another approach is to translate the (limited) radiobiological understanding of a disease into a mechanistic mathematical model to study the doseresponse curve (Preston 2017;Shuryak 2019;Kaiser et al 2021). Stouten et al (2021) presented a mathematical model to quantify the dose-response curve of the major radiation-induced acute myeloid leukemia (rAML) pathway in photon-irradiated male CBA/H mice. These mice have been used extensively to study rAML due to very low background incidence, reproducible maximum rAML induction of about 20% following 3 Gy of whole-body exposure, and histopathological features similar to human AML (Major and Mole 1978;Verbiest et al 2015).…”

Section: Introductionmentioning

confidence: 99%

“…Based on the presented model, experiments are proposed to possibly detect whether HRS affects low-dose rAML incidence. Furthermore, the computationally intensive stochastic rAML model from Stouten et al (2021) was redesigned such that the dose-response curve can be calculated almost instantaneously.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Hyper-radiosensitivity affects low-dose acute myeloid leukemia incidence in a mathematical model

Stouten

Balkenende

Roobol

et al. 2022

Radiat Environ Biophys

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In vitro experiments show that the cells possibly responsible for radiation-induced acute myeloid leukemia (rAML) exhibit low-dose hyper-radiosensitivity (HRS). In these cells, HRS is responsible for excess cell killing at low doses. Besides the endpoint of cell killing, HRS has also been shown to stimulate the low-dose formation of chromosomal aberrations such as deletions. Although HRS has been investigated extensively, little is known about the possible effect of HRS on low-dose cancer risk. In CBA mice, rAML can largely be explained in terms of a radiation-induced Sfpi1 deletion and a point mutation in the remaining Sfpi1 gene copy. The aim of this paper is to present and quantify possible mechanisms through which HRS may influence low-dose rAML incidence in CBA mice. To accomplish this, a mechanistic rAML CBA mouse model was developed to study HRS-dependent AML onset after low-dose photon irradiation. The rAML incidence was computed under the assumptions that target cells: (1) do not exhibit HRS; (2) HRS only stimulates cell killing; or (3) HRS stimulates cell killing and the formation of the Sfpi1 deletion. In absence of HRS (control), the rAML dose-response curve can be approximated with a linear-quadratic function of the absorbed dose. Compared to the control, the assumption that HRS stimulates cell killing lowered the rAML incidence, whereas increased incidence was observed at low doses if HRS additionally stimulates the induction of the Sfpi1 deletion. In conclusion, cellular HRS affects the number of surviving pre-leukemic cells with an Sfpi1 deletion which, depending on the HRS assumption, directly translates to a lower/higher probability of developing rAML. Low-dose HRS may affect cancer risk in general by altering the probability that certain mutations occur/persist.

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Section: Background Of the Modelmentioning

confidence: 99%

Section: Background Of the Modelmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Hyper-radiosensitivity affects low-dose acute myeloid leukemia incidence in a mathematical model

Stouten

Balkenende

Roobol

et al. 2022

Radiat Environ Biophys

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“…The target cells for radiation-induced leukaemia are most likely the HSPCs, since their long-life span allows the accumulation of radiation damage which could compromise their genomic integrity and potentially give rise to leukemogenesis [17][18][19] . Several experimental studies on HSPCs have already illustrated that low dose IR exposure can lead to impaired self-renewal capacity, long-term deleterious effects and cell death 17,20,21 .…”

Section: Introductionmentioning

confidence: 99%

DNA Damage Response of Haematopoietic Stem and Progenitor Cells to High-LET Neutron Irradiation

Engelbrecht

Ndimba

Kock

et al. 2021

Preprint

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The radiosensitivity of haematopoietic stem and progenitor cells (HSPCs) to neutron radiation remains largely underexplored, notwithstanding their potential role as target cells for radiation-induced leukemogenesis. New insights are required for radiation protection purposes, particularly for aviation, space missions, nuclear accidents and even particle therapy. In this study, HSPCs (CD34+ cells) were isolated from umbilical cord blood and irradiated with 60Co γ-rays (photons) and high energy p(66)/Be(40) neutrons. At 2 hours post-irradiation, a significantly higher number of 1.28 ± 0.12 γ-H2AX foci/cell was observed after 0.5 Gy neutrons compared to 0.84 ± 0.14 foci/cell for photons, but this decreased to similar levels for both radiation qualities after 18 hours. However, a signficant difference in late apoptosis was observed between photon and neutron irradiation at 18 hours, 43.17 ± 6.10 % versus 55.55 ± 4.87 %, respectively. A significant increase in cytogenetic damage was observed after both 0.5 and 1 Gy neutron irradiation compared to photons, while there was no difference in the nuclear division index between both radiation qualities. The results point towards a higher induction of DNA damage after neutron irradiation in HSPCs followed by error-prone DNA repair, which contributes to genomic instability and a higher risk of leukemogenesis.

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Therapeutic potential of low dose ionizing radiation against cancer, dementia, and diabetes: evidences from epidemiological, clinical, and preclinical studies

2023

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The growing use of ionizing radiation (IR)-based diagnostic and treatment methods has been linked to increasing chronic diseases among patients and healthcare professionals. However, multiple factors such as IR dose, dose-rate, and duration of exposure influence the IR-induced chronic effects. The predicted links between low-dose ionizing radiation (LDIR) and health risks are controversial due to the non-availability of direct human studies. The studies pertaining to LDIR effects have importance in public health as exposure to background LDIR is routine. It has been anticipated that data from epidemiological and clinical reports and results of preclinical studies can resolve this controversy and help to clarify the notion of LDIR-associated health risks. Accumulating scientific literature shows reduced cancer risk, cancer-related deaths, curtailed neuro-impairments, improved neural functions, and reduced diabetes-related complications after LDIR exposure. In addition, it was found to alter evolutionarily conserved stress response pathways. However, the picture of molecular signaling pathways in LDIR responses is unclear. Besides, there is limited/no information on biomarkers of epidemiological LDIR exposure. Therefore, the present review discusses epidemiological, clinical, and preclinical studies on LDIR-induced positive effects in three chronic diseases (cancer, dementia, and diabetes) and their associated molecular mechanisms. The knowledge of LDIR response mechanisms may help to devise LDIR-based therapeutic modalities to stop disease progression. Modulation of these pathways may be helpful in developing radiation resistance among humans. However, more clinical evidence with additional biochemical, cellular, and molecular data and exploring the side effects of LDIR are the major areas of future research. Supplementary Information The online version contains supplementary material available at 10.1007/s11033-022-08211-5.

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

Cited by 9 publications

References 51 publications

Hyper-radiosensitivity affects low-dose acute myeloid leukemia incidence in a mathematical model

Hyper-radiosensitivity affects low-dose acute myeloid leukemia incidence in a mathematical model

DNA Damage Response of Haematopoietic Stem and Progenitor Cells to High-LET Neutron Irradiation

Therapeutic potential of low dose ionizing radiation against cancer, dementia, and diabetes: evidences from epidemiological, clinical, and preclinical studies

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