Brown Natalie, Finnon Rosemary, Finnon Paul, McCarron Roisin, Cruz-Garcia Lourdes, O'Brien Grainne, Herbert Eleanor, Scudamore Cheryl L, Morel Edouard, Badie Christophe
Cancer Mechanisms and Biomarkers Group Radiation Effects Department, Radiation, Chemical and Environmental Hazards, UK Health Security Agency (UKHSA), Didcot OX11 ORQ, UK.
The Royal Veterinary College, Hatfield, Herts AL9 7TA, UK.
iScience. 2023 Aug 3;26(9):107530. doi: 10.1016/j.isci.2023.107530. eCollection 2023 Sep 15.
Ionizing radiation (IR) is a risk factor for acute myeloid leukemia (rAML). Murine rAMLs feature both hemizygous chromosome 2 deletions (Del2) and point mutations (R235) within the hematopoietic regulatory gene . We generated a heterozygous CBA R235 mouse (CBA) which develops AML with 100% incidence by ∼12 months old and shows a dose-dependent reduction in latency following X-irradiation. These effects are reduced on an AML-resistant C57Bl6 genetic background. CBA reporter mice show increased Gfp expression, indicating compensation for Spm-induced haploinsufficiency. Del2 is always detected in both and rAMLs, indicating that biallelic Spi1 mutation is required for AML. CBA mice show that a single Spm modification is sufficient for initiating AML development with complete penetrance, via the "two-hit" mechanism and this is accelerated by IR exposure. Similar polymorphisms in humans could potentially lead to enhanced susceptibility to IR following medical or environmental exposure.
电离辐射（IR）是急性髓系白血病（rAML）的一个风险因素。小鼠rAML的特征是造血调节基因内存在半合子2号染色体缺失（Del2）和点突变（R235）。我们培育了一种杂合的CBA R235小鼠（CBA），该小鼠在约12个月大时100%发生AML，并且在X射线照射后潜伏期呈剂量依赖性缩短。在抗AML的C57Bl6遗传背景下，这些效应会减弱。CBA报告基因小鼠显示绿色荧光蛋白（Gfp）表达增加，表明对Spm诱导的单倍体不足进行了补偿。在正常细胞和rAML中均始终检测到Del2，这表明AML需要双等位基因Spi1突变。CBA小鼠表明，单个Spm修饰足以通过“两次打击”机制以完全外显率启动AML发展，并且IR暴露会加速这一过程。人类中类似的多态性可能会导致在医疗或环境暴露后对IR的易感性增强。
