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. As humans age, several DNA repair pathways are known to decrease in activity, adding an underappreciated risk to the astronaut population whose age range exceeds 45 years. 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 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. We observed that >64% and >82% of Mlh1+/- mice exposed to 10 and 100 cGy of 56Fe, respectively, developed disease by 18 months after exposure. Irradiated Mlh1+/- mice showed a significantly higher incidence of lymphomagenesis with 56Fe ions compared to ?-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 human leukemias after space radiation, and that countermeasure strategies will be required to adequately protect the astronaut population on the journey to Mars.