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Iron overload induces dysplastic erythropoiesis and features of myelodysplasia in Nrf2-deficient mice

Leukemia volume 38, pages 96–108 (2024)Cite this article

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Abstract

Iron overload (IOL) is hypothesized to contribute to dysplastic erythropoiesis. Several conditions, including myelodysplastic syndrome, thalassemia and sickle cell anemia, are characterized by ineffective erythropoiesis and IOL. Iron is pro-oxidant and may participate in the pathophysiology of these conditions by increasing genomic instability and altering the microenvironment. There is, however, lack of in vivo evidence demonstrating a role of IOL and oxidative damage in dysplastic erythropoiesis. NRF2 transcription factor is the master regulator of antioxidant defenses, playing a crucial role in the cellular response to IOL in the liver. Here, we crossed Nrf2−/− with hemochromatosis (Hfe−/−) or hepcidin-null (Hamp1−/−) mice. Double-knockout mice developed features of ineffective erythropoiesis and myelodysplasia including macrocytic anemia, splenomegaly, and accumulation of immature dysplastic bone marrow (BM) cells. BM cells from Nrf2/Hamp1−/− mice showed increased in vitro clonogenic potential and, upon serial transplantation, recipients disclosed cytopenias, despite normal engraftment, suggesting defective differentiation. Unstimulated karyotype analysis showed increased chromosome instability and aneuploidy in Nrf2/Hamp1−/− BM cells. In HFE-related hemochromatosis patients, NRF2 promoter SNP rs35652124 genotype TT (predicted to decrease NRF2 expression) associated with increased MCV, consistent with erythroid dysplasia. Our results suggest that IOL induces ineffective erythropoiesis and dysplastic hematologic features through oxidative damage in Nrf2-deficient cells.

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Fig. 1: Development of macrocytic anemia in aged Nrf2/Hfe−/− mice.
Fig. 2: Evidence of myelodysplasia in Nrf2/Hfe−/− mice and increased susceptibility of Nrf2−/− RBCs to phagocytosis in IOL.
Fig. 3: Development of macrocytic anemia, reticulocytosis and splenomegaly in Nrf2/Hamp1−/− mice.
Fig. 4: Development of myelodysplastic features in Nrf2/Hamp1−/− BM.
Fig. 5: Development of anemia and thrombocytopenia in recipient mice upon serial transplantation of Nrf2/Hamp1−/− BM.
Fig. 6: The association between NRF2 promoter SNP rs35652124 and the erythroid dysplasia in HC patients.

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Data availability

For original data, please contact tduarte@ibmc.up.pt.

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Acknowledgements

This work was financed by: National Funds through FCT - Fundação para a Ciência e a Tecnologia, I.P., under the project UIDB/04293/2020; FEDER - Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020 - Operacional Programme for Competitiveness and Internationalization (POCI), Portugal 2020, and by Portuguese funds through FCT (FCOMP-01-0124-FEDER-028447, PTDC/BIM-MET/0739/2012) to TLD; and by Forum Hematológico do Norte (FHN - 2021 - MDS NRF2 Iron) to GP. This work was funded in part by an EHA Research Grant award granted by the European Hematology Association (to DD) and by Programa Operacional Regional do Norte and co-funded by European Regional Development Fund under the project “The Porto Comprehensive Cancer Center” with the reference NORTE-01-0145-FEDER-072678 - Consórcio PORTO.CCC – Porto.Comprehensive Cancer Center. AMNS is supported by UIDB/50006/2020|UIDP/50006/2020. We would like to thank Dr. Susana Roncon (IPO-Porto) and Dr. Sérgio Lopes (IPO-Porto) for support with the colony assays.

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Authors and Affiliations

  1. i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal

    Tiago L. Duarte, Marta Lopes, Mónica Oliveira, Ana G. Santos, Catarina Vasco, Joana P. Reis, Ana Rita Antunes, Andreia Gonçalves, Ana C. Moreira, Graça Porto & Delfim Duarte

  2. IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal

    Tiago L. Duarte, Marta Lopes, Mónica Oliveira, Ana G. Santos, Catarina Vasco, Joana P. Reis, Ana Rita Antunes, Andreia Gonçalves, Ana C. Moreira & Graça Porto

  3. Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal

    Joana P. Reis & Ana C. Moreira

  4. Serviço de Hematologia e Transplantação de Medula Óssea, Instituto Português de Oncologia do Porto Francisco Gentil, E.P.E. (IPO Porto), Porto, Portugal

    Sérgio Chacim & Delfim Duarte

  5. Laboratório de Citogenética, Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal

    Cláudia Oliveira & Beatriz Porto

  6. Departmento de Patologia Clínica, Centro Hospitalar Universitário São João, Porto, Portugal

    Maria José Teles

  7. LAQV-REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, Porto, Portugal

    André M. N. Silva

  8. LAQV-REQUIMTE, Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal

    André M. N. Silva

  9. MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK

    Ron Schwessinger

  10. MRC WIMM Centre for Computational Biology, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK

    Ron Schwessinger

  11. MRC Translational Immune Discovery Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK

    Hal Drakesmith

  12. Serviço de Anatomia Patológica, IPO Porto, Porto, Portugal

    Rui Henrique

  13. Departamento de Patologia e Imunologia Molecular, Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal

    Rui Henrique & Graça Porto

  14. Serviço de Imuno-hemoterapia, Centro Hospitalar Universitário de Santo António (CHUdSA), Porto, Portugal

    Graça Porto

  15. Departmento de Biomedicina, Faculdade de Medicina da Universidade do Porto (FMUP), Porto, Portugal

    Delfim Duarte

  16. P.CCC - Porto Comprehensive Cancer Center Raquel Seruca, Porto, Portugal

    Delfim Duarte

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  1. Tiago L. Duarte
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Contributions

TLD, ML, MO, CV, AGS, JR, RA, AGS, SC, CO, BP, MJT, AS, RS, and DD performed experiments; TLD, AG, SC, BP, ACM, HD, RH, GP, and DD analyzed results; TLD, GP, and DD designed the research and wrote the paper; all authors proofread and approved the manuscript.

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Correspondence to Tiago L. Duarte or Delfim Duarte.

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Duarte, T.L., Lopes, M., Oliveira, M. et al. Iron overload induces dysplastic erythropoiesis and features of myelodysplasia in Nrf2-deficient mice. Leukemia 38, 96–108 (2024). https://doi.org/10.1038/s41375-023-02067-9

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