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Animal models

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

Leukemiavolume 33pages11351147 (2019) | Download Citation

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 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.

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Acknowledgements

This research was funded by NASA grant NNX14AC95G. We are grateful to all members of NASA Space Radiation Laboratory and support staff at Brookhaven National Laboratory, in particular to Adam Rusek, Chiara La Tessa, and Peter Guida, for their assistance. We are also thankful to shared resources of the Case Comprehensive Cancer Center including Radiation Resources, Integrated Genomics, Cytometry & Microscopy, and Hematopoietic Biorepository & Cellular Therapy. We also thank the generosity of Thomas F. Peterson, Jr.

Funding

This research was funded by NASA grant NNX14AC95G.

Author information

Affiliations

  1. Department of Pharmacology, Case Western Reserve University, Cleveland, OH, USA

    • Rutulkumar Patel
  2. Department of Medicine, Case Western Reserve University, Cleveland, OH, USA

    • Amar Desai
    •  & Stanton L. Gerson
  3. Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA

    • Luchang Zhang
    • , Amar Desai
    •  & Stanton L. Gerson
  4. In Vivo Animal Core Unit for Laboratory Animal Medicine, University of Michigan, Ann Arbor, MI, USA

    • Mark J. Hoenerhoff
    •  & Lucy H. Kennedy
  5. Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH, USA

    • Tomas Radivoyevitch
  6. Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA

    • Yuguang Ban
    • , Xi Steven Chen
    •  & Scott M. Welford
  7. Department of Public Health Sciences, University of Miami, Miami, FL, USA

    • Xi Steven Chen
  8. Department of Radiation Oncology, University of Miami, Miami, FL, USA

    • Scott M. Welford

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The authors declare that they have no conflict of interest.

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Correspondence to Scott M. Welford.

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https://doi.org/10.1038/s41375-018-0269-8