Stem cell transplantation

Impact of Nrf2 expression in reconstituting T-cells of allogeneic hematopoietic stem cell transplanted patients

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Fig. 1: Nrf2 levels in reconstituting T-cells after allo-HSCT.
Fig. 2: Impact of Nrf2 levels on T-cell exhaustion phenotype and clinical outcome.

References

  1. 1.

    Singh AK, McGuirk JP. Allogeneic stem cell transplantation: a historical and scientific overview. Cancer Res. 2016;76:6445–51.

    CAS  Article  Google Scholar 

  2. 2.

    Ma Q. Role of nrf2 in oxidative stress and toxicity. Annu Rev Pharm Toxicol. 2013;53:401–26.

    CAS  Article  Google Scholar 

  3. 3.

    Merchant AA, Singh A, Matsui W, Biswal S. The redox-sensitive transcription factor Nrf2 regulates murine hematopoietic stem cell survival independently of ROS levels. Blood. 2011;118:6572–9.

    CAS  Article  Google Scholar 

  4. 4.

    Lin P, Ren Y, Yan X, Luo Y, Zhang H, Kesarwani M, et al. The high NRF2 expression confers chemotherapy resistance partly through up-regulated DUSP1 in myelodysplastic syndromes. Haematologica. 2019;104:485–96.

    CAS  Article  Google Scholar 

  5. 5.

    Suzuki T, Murakami S, Biswal SS, Sakaguchi S, Harigae H, Yamamoto M, et al. Systemic activation of NRF2 alleviates lethal autoimmune inflammation in scurfy mice. Mol Cell Biol. 2017;37:e00063–17.

  6. 6.

    Carlstrom KE, Ewing E, Granqvist M, Gyllenberg A, Aeinehband S, Enoksson SL, et al. Therapeutic efficacy of dimethyl fumarate in relapsing-remitting multiple sclerosis associates with ROS pathway in monocytes. Nat Commun. 2019;10:3081.

    Article  Google Scholar 

  7. 7.

    Tsai JJ, Velardi E, Shono Y, Argyropoulos KV, Holland AM, Smith OM, et al. Nrf2 regulates CD4(+) T cell-induced acute graft-versus-host disease in mice. Blood. 2018;132:2763–74.

    CAS  Article  Google Scholar 

  8. 8.

    Han J, Ma S, Gong H, Liu S, Lei L, Hu B, et al. Inhibition of acute graft-versus-host disease with retention of graft-versus-tumor effects by dimethyl fumarate. Front Immunol. 2017;8:1605.

    Article  Google Scholar 

  9. 9.

    Melenhorst JJ, Tian X, Xu D, Sandler NG, Scheinberg P, Biancotto A, et al. Cytopenia and leukocyte recovery shape cytokine fluctuations after myeloablative allogeneic hematopoietic stem cell transplantation. Haematologica. 2012;97:867–73.

    CAS  Article  Google Scholar 

  10. 10.

    Sofi MH, Wu Y, Schutt SD, Dai M, Daenthanasanmak A, Heinrichs Voss J, et al. Thioredoxin-1 confines T cell alloresponse and pathogenicity in graft-versus-host disease. J Clin Invest. 2019;129:2760–74.

    Article  Google Scholar 

  11. 11.

    Kim DH, Kim JG, Sohn SK, Sung WJ, Suh JS, Lee KS, et al. Clinical impact of early absolute lymphocyte count after allogeneic stem cell transplantation. Br J Haematol. 2004;125:217–24.

    Article  Google Scholar 

  12. 12.

    Noel S, Martina MN, Bandapalle S, Racusen LC, Potteti HR, Hamad AR, et al. T lymphocyte-specific activation of Nrf2 protects from AKI. J Am Soc Nephrol. 2015;26:2989–3000.

    CAS  Article  Google Scholar 

  13. 13.

    Huang W, Chao NJ. Memory T cells: a helpful guard for allogeneic hematopoietic stem cell transplantation without causing graft-versus-host disease. Hematol Oncol Stem Cell Ther. 2017;10:211–9.

    CAS  Article  Google Scholar 

  14. 14.

    Zeiser R, Vago L. Mechanisms of immune escape after allogeneic hematopoietic cell transplantation. Blood. 2019;133:1290–7.

    CAS  Article  Google Scholar 

  15. 15.

    Noviello M, Manfredi F, Ruggiero E, Perini T, Oliveira G, Cortesi F, et al. Bone marrow central memory and memory stem T-cell exhaustion in AML patients relapsing after HSCT. Nat Commun. 2019;10:1065.

    Article  Google Scholar 

  16. 16.

    Yoshizawa S, Umezu T, Saitoh Y, Gotoh M, Akahane D, Kobayashi C, et al. Exosomal miRNA signatures for late-onset acute graft-versus-host disease in allogenic hematopoietic stem cell transplantation. Int J Mol Sci. 2018;19:2493.

  17. 17.

    Weiss G, Schwaighofer H, Herold M, Nachbaur D, Wachter H, Niederwieser D, et al. Nitric oxide formation as predictive parameter for acute graft-versus-host disease after human allogeneic bone marrow transplantation. Transplantation. 1995;60(Dec):1239–44.

    CAS  Article  Google Scholar 

  18. 18.

    Hartikainen JM, Tengstrom M, Kosma VM, Kinnula VL, Mannermaa A, Soini Y. Genetic polymorphisms and protein expression of NRF2 and Sulfiredoxin predict survival outcomes in breast cancer. Cancer Res. 2012;72:5537–46.

    CAS  Article  Google Scholar 

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Acknowledgements

We are grateful to the patients, their families, and referring physicians who made this study possible. We thank Alina Kämpf (Core Unit Cell Sorting and Immunomonitoring, Erlangen) for excellent support. FK, RB, RJ, AM, and DM were funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - Project-ID 324392634 - TRR 221.

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FK performed research, analyzed data, and helped writing the manuscript. AS, RL, MB, BJ, and RB performed research and analyzed data. SV and WR provided patient material and clinical data. AM helped designing the study. DM designed the study, analyzed data, and wrote the manuscript.

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Correspondence to Dimitrios Mougiakakos.

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Karl, F., Stoll, A., Böttcher-Loschinski, R. et al. Impact of Nrf2 expression in reconstituting T-cells of allogeneic hematopoietic stem cell transplanted patients. Leukemia (2020). https://doi.org/10.1038/s41375-020-0956-0

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