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

Leukemia volume 33, pages 1135–1147 (2019)Cite this article

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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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References

  1. Cucinotta FA, Schimmerling W, Wilson JW, Peterson LE, Badhwar GD, Saganti PB, et al. Space radiation cancer risks and uncertainties for Mars missions. Radiat Res. 2001;156(5 Pt 2):682–8.

    Article  CAS  Google Scholar 

  2. Edwards AA. RBE of radiations in space and the implications for space travel. Phys Med: PM: Int J devoted the Appl Phys Med Biol: Off J Ital Assoc Biomed Phys. 2001;17(Suppl 1):147–52.

    Google Scholar 

  3. Schimmerling W, Cucinotta FA, Wilson JW. Radiation risk and human space exploration. Adv Space Res: Off J Comm Space Res. 2003;31:27–34.

    Article  CAS  Google Scholar 

  4. Heinrich W, Roesler S, Schraube H. Physics of cosmic radiation fields. Radiat Prot Dosim. 1999;86:253–8.

    Article  CAS  Google Scholar 

  5. Chancellor JC, Scott GB, Sutton JP. Space radiation: The number one risk to astronaut health beyond low earth orbit. Life. 2014;4:491–510.

    Article  Google Scholar 

  6. V B. Health effects of exposure to low levels of ionizing radiation. 1990 20140718 ISBN- 0309039959 ISBN- 0309039975.

  7. Bielefeldt-Ohmann H, Genik PC, Fallgren CM, Ullrich RL, Weil MM. Animal studies of charged particle-induced carcinogenesis. Health Phys. 2012;103:568–76.

    Article  CAS  Google Scholar 

  8. Weil MM, Bedford JS, Bielefeldt-Ohmann H, Ray FA, Genik PC, Ehrhart EJ, et al. Incidence of acute myeloid leukemia and hepatocellular carcinoma in mice irradiated with 1 GeV/nucleon (56)Fe ions. Radiat Res. 2009;172:213–9.

    Article  CAS  Google Scholar 

  9. Datta K, Suman S, Kallakury BV, Fornace AJ Jr.. Exposure to heavy ion radiation induces persistent oxidative stress in mouse intestine. PLoS One. 2012;7:e42224.

    Article  CAS  Google Scholar 

  10. Wei K, Clark AB, Wong E, Kane MF, Mazur DJ, Parris T, et al. Inactivation of Exonuclease 1 in mice results in DNA mismatch repair defects, increased cancer susceptibility, and male and female sterility. Genes & Dev. 2003;17:603–14.

    Article  CAS  Google Scholar 

  11. Iyer RR, Pluciennik A, Burdett V, Modrich PL. DNA mismatch repair: functions and mechanisms. Chem Rev. 2006;106:302–23.

    Article  CAS  Google Scholar 

  12. Fritzell JA, Narayanan L, Baker SM, Bronner CE, Andrew SE, Prolla TA, et al. Role of DNA mismatch repair in the cytotoxicity of ionizing radiation. Cancer Res. 1997;57:5143–7.

    CAS  PubMed  Google Scholar 

  13. Mazurek A, Berardini M, Fishel R. Activation of human MutS homologs by 8-oxo-guanine DNA damage. J Biol Chem. 2002;277:8260–6.

    Article  CAS  Google Scholar 

  14. Macpherson P, Barone F, Maga G, Mazzei F, Karran P, Bignami M. 8-oxoguanine incorporation into DNA repeats in vitro and mismatch recognition by MutSalpha. Nucl Acids Res. 2005;33:5094–105.

    Article  CAS  Google Scholar 

  15. Vilar E, Gruber SB. Microsatellite instability in colorectal cancer-the stable evidence. Nat Rev Clin Oncol. 2010;7:153–62.

    Article  CAS  Google Scholar 

  16. Kinzler KW, Vogelstein B. Cancer-susceptibility genes. Gatekeepers and caretakers. Nature. 1997;386:761

    Article  CAS  Google Scholar 

  17. Piao JS, Nakatsu Y, Ohno M, Taguchi K, Tsuzuki T. Mismatch repair deficient mice show susceptibility to oxidative stress-induced intestinal carcinogenesis. Int J Biol Sci. 2014;10:73–9.

    Article  Google Scholar 

  18. Qing Y, Gerson SL. Mismatch repair deficient hematopoietic stem cells are preleukemic stem cells. PLoS One. 2017;12:e0182175.

    Article  Google Scholar 

  19. Ma Y, Chen Y, Petersen I. Expression and promoter DNA methylation of MLH1 in colorectal cancer and lung cancer. Pathol Res Pract. 2017;213:333–8.

    Article  CAS  Google Scholar 

  20. Gutierrez VF, Marcos CA, Llorente JL, Guervos MA, Iglesias FD, Tamargo LA, et al. Genetic profile of second primary tumors and recurrences in head and neck squamous cell carcinomas. Head & neck. 2012;34:830–9.

    Article  Google Scholar 

  21. Stark AM, Doukas A, Hugo HH, Hedderich J, Hattermann K, Maximilian Mehdorn H, et al. Expression of DNA mismatch repair proteins MLH1, MSH2, and MSH6 in recurrent glioblastoma. Neurol Res. 2015;37:95–105.

    Article  CAS  Google Scholar 

  22. Cosgrove CM, Cohn DE, Hampel H, Frankel WL, Jones D, McElroy JP, et al. Epigenetic silencing of MLH1 in endometrial cancers is associated with larger tumor volume, increased rate of lymph node positivity and reduced recurrence-free survival. Gynecol Oncol. 2017;146:588–95.

    Article  CAS  Google Scholar 

  23. Kenyon J, Fu P, Lingas K, Thomas E, Saurastri A, Santos Guasch G, et al. Humans accumulate microsatellite instability with acquired loss of MLH1 protein in hematopoietic stem and progenitor cells as a function of age. Blood. 2012;120:3229–36.

    Article  CAS  Google Scholar 

  24. Kenyon J, Nickel-Meester G, Qing Y, Santos-Guasch G, Drake E, Pingfu Fu, et al. Epigenetic Loss of MLH1 Expression in Normal Human Hematopoietic Stem Cell Clones is Defined by the Promoter CpG Methylation Pattern Observed by High-Throughput Methylation Specific Sequencing. Int J Stem Cell Res Therapy. 2016;3:031.

  25. Edelmann W, Cohen PE, Kane M, Lau K, Morrow B, Bennett S, et al. Meiotic pachytene arrest in MLH1-deficient mice. Cell. 1996;85:1125–34.

    Article  CAS  Google Scholar 

  26. Bacher JW, Abdel Megid WM, Kent-First MG, Halberg RB. Use of mononucleotide repeat markers for detection of microsatellite instability in mouse tumors. Mol Carcinog. 2005;44:285–92.

    Article  CAS  Google Scholar 

  27. Bolger AM, Lohse M, Usadel B. Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics. 2014;30:2114–20.

    Article  CAS  Google Scholar 

  28. Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009;25:1754–60.

    Article  CAS  Google Scholar 

  29. DePristo MA, Banks E, Poplin R, Garimella KV, Maguire JR, Hartl C, et al. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet. 2011;43:491.

    Article  CAS  Google Scholar 

  30. Cibulskis K, Lawrence MS, Carter SL, Sivachenko A, Jaffe D, Sougnez C, et al. Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples. Nat Biotechnol. 2013;31:213–9.

    Article  CAS  Google Scholar 

  31. Obenchain V, Lawrence M, Carey V, Gogarten S, Shannon P, Morgan M. VariantAnnotation: a Bioconductor package for exploration and annotation of genetic variants. Bioinformatics. 2014;30:2076–8.

    Article  CAS  Google Scholar 

  32. Tokairin Y, Kakinuma S, Arai M, Nishimura M, Okamoto M, Ito E, et al. Accelerated growth of intestinal tumours after radiation exposure in Mlh1-knockout mice: evaluation of the late effect of radiation on a mouse model of HNPCC. Int J Exp Pathol. 2006;87:89–99.

    Article  Google Scholar 

  33. Edelmann W, Yang K, Kuraguchi M, Heyer J, Lia M, Kneitz B, et al. Tumorigenesis in Mlh1 and Mlh1/Apc1638N mutant mice. Cancer Res. 1999;59:1301–7.

    CAS  PubMed  Google Scholar 

  34. Yao X, Buermeyer AB, Narayanan L, Tran D, Baker SM, Prolla TA, et al. Different mutator phenotypes in Mlh1- versus Pms2-deficient mice. Proc Natl Acad Sci USA. 1999;96:6850–5.

    Article  CAS  Google Scholar 

  35. Scott DW, Gascoyne RD. The tumour microenvironment in B cell lymphomas. Nat Rev Cancer. 2014;14:517–34.

    Article  CAS  Google Scholar 

  36. Hause RJ, Pritchard CC, Shendure J, Salipante SJ. Classification and characterization of microsatellite instability across 18 cancer types. Nat Med. 2016;22:1342–50.

    Article  CAS  Google Scholar 

  37. Fan X, Li Y, Zhang Y, Sang M, Cai J, Li Q, et al. High Mutation Levels are Compatible with Normal Embryonic Development in Mlh1-Deficient Mice. Radiat Res. 2016;186:377–84.

    Article  CAS  Google Scholar 

  38. He D, Chen Y, Li H, Furuya M, Ikehata H, Uehara Y, et al. Role of the Msh2 gene in genome maintenance and development in mouse fetuses. Mutat Res. 2012;734:50–5.

    Article  CAS  Google Scholar 

  39. Dovat S, Song C, Payne KJ, Li Z. Ikaros, CK2 kinase, and the road to leukemia. Mol Cell Biochem. 2011;356:201–7.

    Article  CAS  Google Scholar 

  40. Payne KJ, Dovat S. Ikaros and tumor suppression in acute lymphoblastic leukemia. Crit Rev Oncog. 2011;16:3–12.

    Article  Google Scholar 

  41. Gutierrez A, Kentsis A, Sanda T, Holmfeldt L, Chen SC, Zhang J, et al. The BCL11B tumor suppressor is mutated across the major molecular subtypes of T-cell acute lymphoblastic leukemia. Blood. 2011;118:4169–73.

    Article  CAS  Google Scholar 

  42. Lopez-Nieva P, Vaquero C, Fernandez-Navarro P, Gonzalez-Sanchez L, Villa-Morales M, Santos J, et al. EPHA7, a new target gene for 6q deletion in T-cell lymphoblastic lymphomas. Carcinogenesis. 2012;33:452–8.

    Article  CAS  Google Scholar 

  43. Cucinotta FA, Nikjoo H, Goodhead DT. Model for radial dependence of frequency distributions for energy imparted in nanometer volumes from HZE particles. Radiat Res. 2000;153:459–68.

    Article  CAS  Google Scholar 

  44. Mirsch J, Tommasino F, Frohns A, Conrad S, Durante M, Scholz M, et al. Direct measurement of the 3-dimensional DNA lesion distribution induced by energetic charged particles in a mouse model tissue. Proc Natl Acad Sci USA. 2015;112:12396–401.

    Article  CAS  Google Scholar 

  45. Weil MM, Ray FA, Genik PC, Yu Y, McCarthy M, Fallgren CM, et al. Effects of 28Si ions, 56Fe ions, and protons on the induction of murine acute myeloid leukemia and hepatocellular carcinoma. PLoS ONE. 2014;9:e104819.

    Article  Google Scholar 

  46. Suman S, Kumar S, Moon BH, Strawn SJ, Thakor H, Fan Z, et al. Relative Biological Effectiveness of Energetic Heavy Ions for Intestinal Tumorigenesis Shows Male Preponderance and Radiation Type and Energy Dependence in APC(1638N/ + ) Mice. Int J Radiat Oncol Biol Phys. 2016;95:131–8.

    Article  CAS  Google Scholar 

  47. Wang X, Farris Iii AB, Wang P, Zhang X, Wang H, Wang Y. Relative effectiveness at 1 gy after acute and fractionated exposures of heavy ions with different linear energy transfer for lung tumorigenesis. Radiat Res. 2015;183:233–9.

    Article  CAS  Google Scholar 

  48. Rithidech KN, Honikel LM, Reungpathanaphong P, Tungjai M, Jangiam W, Whorton EB. Late-occurring chromosome aberrations and global DNA methylation in hematopoietic stem/progenitor cells of CBA/CaJ mice exposed to silicon ((28)Si) ions. Mutat Res. 2015;781:22–31.

    Article  CAS  Google Scholar 

  49. Kennedy EM, Powell DR, Li Z, Bell JSK, Barwick BG, Feng H, et al. Galactic Cosmic Radiation Induces Persistent Epigenome Alterations Relevant to HumanLung Cancer. Sci Rep. 2018;8:6709.

    Article  CAS  Google Scholar 

  50. Sridharan DM, Asaithamby A, Bailey SM, Costes SV, Doetsch PW, Dynan WS, et al. Understanding cancer development processes after HZE-particle exposure: roles of ROS, DNA damage repair and inflammation. Radiat Res. 2015;183:1–26.

    Article  CAS  Google Scholar 

  51. Chang J, Luo Y, Wang Y, Pathak R, Sridharan V, Jones T, et al. Low doses of oxygen ion irradiation cause acute damage to hematopoietic cells in mice. PLoS ONE. 2016;11:e0158097.

    Article  Google Scholar 

  52. Eccleston J, Yan C, Yuan K, Alt FW, Selsing E. Mismatch repair proteins MSH2, MLH1, and EXO1 are important for class-switch recombination events occurring in B cells that lack nonhomologous end joining. J Immunol. 2011;186:2336–43.

    Article  CAS  Google Scholar 

  53. Chahwan R, van Oers JM, Avdievich E, Zhao C, Edelmann W, Scharff MD, et al. The ATPase activity of MLH1 is required to orchestrate DNA double-strand breaks and end processing during class switch recombination. J Exp Med. 2012;209:671–8.

    Article  CAS  Google Scholar 

  54. Gutmann DH, Winkeler E, Kabbarah O, Hedrick N, Dudley S, Goodfellow PJ, et al. Mlh1 deficiency accelerates myeloid leukemogenesis in neurofibromatosis 1 (Nf1) heterozygous mice. Oncogene. 2003;22:4581–5.

    Article  CAS  Google Scholar 

  55. Fang Y, Tsao CC, Goodman BK, Furumai R, Tirado CA, Abraham RT, et al. ATR functions as a gene dosage-dependent tumor suppressor on a mismatch repair-deficient background. EMBO J. 2004;23:3164–74.

    Article  CAS  Google Scholar 

  56. Rodman C, Almeida-Porada G, George SK, Moon J, Soker S, Pardee T, et al. In vitro and in vivo assessment of direct effects of simulated solar and galactic cosmic radiation on human hematopoietic stem/progenitor cells. Leukemia. 2017;31:1398–407.

    Article  CAS  Google Scholar 

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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.

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Authors and 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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Patel, R., Zhang, L., Desai, A. et al. Mlh1 deficiency increases the risk of hematopoietic malignancy after simulated space radiation exposure. Leukemia 33, 1135–1147 (2019). https://doi.org/10.1038/s41375-018-0269-8

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