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

Abstract

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 56 Fe ion space-like radiation. Irradiated Mlh1 +/− mice showed a significantly higher incidence of lymphomagenesis with 56 Fe 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.

A Longitudinal Epigenetic Aging and Leukocyte Analysis of Simulated Space Travel: The Mars-500 Mission

“…Crew members on a space mission and astronauts living on the International Space Station (ISS) can remain in space for many months at a time, where they experience a unique combination of stressors known to impact aging processes, including social isolation, confinement, microgravity, and cosmic radiation ( Giovanetti et al, 2020 ; Welsh et al, 2019 ; Kehler et al, 2019 ; Pantell et al, 2013 ; Tanskanen and Anttila, 2016 ). Although the potential negative impact of these stressors is well appreciated, the financial and physical demands of studying human aging biology in outer space have resigned some aspects of aging research to animal models or cell cultures ( Demontis et al, 2017 ; Patel et al, 2019 ). Nevertheless, research reporting mixed or unexpected relationships of space exposures with aging-related outcomes in human subjects provides continued motivation for research efforts that explicitly focus on studying humans ( Strollo et al, 2018 ).…”

RNA‐Seq analysis of differentially expressed genes relevant to mismatch repair in aging hematopoietic stem‐progenitor cells

“…Recent results from Welford SM’ laboratory have demonstrated that acquired MMR deficiency and increased microsatellite instability, a commonly observed marker of DNA MMR deficiency in human hematopoietic stem and progenitor cells is age‐related, attributable to progressive loss of Mlh1 through promoter hypermethylation . The data show that as many as 30% of HSCs in healthy individuals have lost MLH1 by 45 years of age …”

“…3 However, studies on the relationship between MMR and HSC aging are not so much. [4][5][6][7] In this paper, we used RNA-Seq technology and an old hematopoietic stem and progenitor cells (HSPCs) model in vitro to analyze differential expressions of MMR-related genes in aged HSPCs, so as to explore the mechanism of DNA MMR injury in HSC aging.…”

Activation of Notch1 drives the development of radiation-induced thymic lymphoma in p53 wild-type mice

“…Collectively, these genomic studies provide compelling evidence to support a model in humans and mice without germline mutations where the formation of hematologic malignancies following exposure to ionizing radiation occurs through a non-cell-autonomous mechanism 8,46,47 . However, for individuals harboring germline mutations in DNA damage response genes, such as p53 and Mlh1 , ionizing radiation may cause blood cancers through a more direct cell-autonomous effect by increasing genomic instability in tumor-initiating cells 13,14,45 .…”

“…Moreover, results from WES and whole-genome sequencing show distinct mutational patterns in radiation-induced cancers that develop in wild-type mice versus mice with pre-existing germline mutations. For example, using a mouse model of B-cell lymphoma, Patel et al found that gamma-rays and heavy ion ( 56 Fe) radiation markedly increased the number of insertions and deletions (indels) per tumor only in mice lacking one allele of the mismatch repair gene Mlh1 (Mlh1 +/- ) 13 . Also, using mice carrying different loss of function alleles of the tumor suppressor p53, Li et al observed that the genomic landscape of radiation-induced cancers is influenced by radiation quality, germline p53 deficiency and tissue/cell of origin 14 .…”