Mlh1 deficiency increases the risk of hematopoietic malignancy after simulated space radiation exposure

Cancer-causing genome instability is a major concern during space travel due to exposure of astronauts to potent sources of high-linear energy transfer (LET) ionizing radiation. Hematopoietic stem cells (HSCs) are particularly susceptible to genotoxic stress, and accumulation of damage can lead to HSC dysfunction and oncogenesis. Our group recently demonstrated that aging human HSCs accumulate microsatellite instability coincident with loss of MLH1, a DNA Mismatch Repair (MMR) protein, which could reasonably predispose to radiation-induced HSC malignancies. Therefore, in an effort to reduce risk uncertainty for cancer development during deep space travel, we employed an Mlh1+/- mouse model to study the effects high-LET 56Fe ion space-like radiation. Irradiated Mlh1+/- mice showed a significantly higher incidence of lymphomagenesis with 56Fe ions compared to γ-rays and unirradiated mice, and malignancy correlated with increased MSI in the tumors. In addition, whole-exome sequencing analysis revealed high SNVs and INDELs in lymphomas being driven by loss of Mlh1 and frequently mutated genes had a strong correlation with human leukemias. Therefore, the data suggest that age-related MMR deficiencies could lead to HSC malignancies after space radiation, and that countermeasure strategies will be required to adequately protect the astronaut population on the journey to Mars.

太空旅行过程中，宇航员会暴露于强高传能线密度（high-linear energy transfer, LET）电离辐射源，由此引发的致癌性基因组不稳定是一项重大安全关切。造血干细胞（hematopoietic stem cells, HSCs）对遗传毒性应激尤为易感，损伤累积可导致造血干细胞功能异常与肿瘤发生。本团队近期研究证实，衰老的人类造血干细胞会伴随DNA错配修复（DNA Mismatch Repair, MMR）蛋白MLH1的缺失，出现微卫星不稳定性（microsatellite instability, MSI），这一改变可能会使个体更易罹患辐射诱导的造血干细胞恶性肿瘤。为降低深空旅行中癌症发生的风险不确定性，我们采用Mlh1+/-小鼠模型，探究高传能线密度铁-56（56Fe）离子类太空辐射的生物学效应。经铁-56离子照射的Mlh1+/-小鼠，其淋巴瘤发生率显著高于γ射线照射组与未照射对照组，且肿瘤恶性程度与瘤内微卫星不稳定性升高呈显著相关。此外，全外显子组测序分析显示，淋巴瘤中存在高水平的单核苷酸变异（single nucleotide variants, SNVs）与插入缺失变异（insertions and deletions, INDELs），且这些变异由Mlh1缺失驱动；同时，高频突变基因与人类白血病存在显著相关性。综上，本研究数据表明，年龄相关的错配修复缺陷可能会导致太空辐射后造血干细胞恶性肿瘤的发生，因此需要制定相应防护策略，以充分保障火星之旅中航天员群体的健康安全。