دورية أكاديمية
Iron overload induces dysplastic erythropoiesis and features of myelodysplasia in Nrf2-deficient mice.
| العنوان: | Iron overload induces dysplastic erythropoiesis and features of myelodysplasia in Nrf2-deficient mice. |
|---|---|
| المؤلفون: | Duarte TL; i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal. tduarte@ibmc.up.pt.; IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal. tduarte@ibmc.up.pt., Lopes M; i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.; IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal., Oliveira M; i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.; IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal., Santos AG; i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.; IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal., Vasco C; i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.; IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal., Reis JP; i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.; IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal.; Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal., Antunes AR; i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.; IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal., Gonçalves A; i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.; IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal., Chacim S; Serviço de Hematologia e Transplantação de Medula Óssea, Instituto Português de Oncologia do Porto Francisco Gentil, E.P.E. (IPO Porto), Porto, Portugal., Oliveira C; Laboratório de Citogenética, Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal., Porto B; Laboratório de Citogenética, Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal., Teles MJ; Departmento de Patologia Clínica, Centro Hospitalar Universitário São João, Porto, Portugal., Moreira AC; i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.; IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal.; Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal., Silva AMN; LAQV-REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, Porto, Portugal.; LAQV-REQUIMTE, Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal., Schwessinger R; MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.; MRC WIMM Centre for Computational Biology, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK., Drakesmith H; MRC Translational Immune Discovery Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK., Henrique R; Serviço de Anatomia Patológica, IPO Porto, Porto, Portugal.; Departamento de Patologia e Imunologia Molecular, Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal., Porto G; i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.; IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal.; Departamento de Patologia e Imunologia Molecular, Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal.; Serviço de Imuno-hemoterapia, Centro Hospitalar Universitário de Santo António (CHUdSA), Porto, Portugal., Duarte D; i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal. delfimd@med.up.pt.; Serviço de Hematologia e Transplantação de Medula Óssea, Instituto Português de Oncologia do Porto Francisco Gentil, E.P.E. (IPO Porto), Porto, Portugal. delfimd@med.up.pt.; Departmento de Biomedicina, Faculdade de Medicina da Universidade do Porto (FMUP), Porto, Portugal. delfimd@med.up.pt.; P.CCC - Porto Comprehensive Cancer Center Raquel Seruca, Porto, Portugal. delfimd@med.up.pt. |
| المصدر: | Leukemia [Leukemia] 2024 Jan; Vol. 38 (1), pp. 96-108. Date of Electronic Publication: 2023 Oct 19. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Nature Publishing Group, Specialist Journals Country of Publication: England NLM ID: 8704895 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5551 (Electronic) Linking ISSN: 08876924 NLM ISO Abbreviation: Leukemia Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2000- : London : Nature Publishing Group, Specialist Journals Original Publication: [Baltimore, Md.] : Williams & Wilkins, [c1987- |
| مواضيع طبية MeSH: | Anemia*/metabolism , Hemochromatosis*/genetics , Hemochromatosis*/metabolism , Iron Overload*/genetics , Iron Overload*/metabolism , Myelodysplastic Syndromes*/genetics, Animals ; Humans ; Mice ; Erythropoiesis/genetics ; Mice, Knockout ; NF-E2-Related Factor 2/genetics ; NF-E2-Related Factor 2/metabolism |
| مستخلص: | 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. (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.) |
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Am J Cancer Res. 2021;11:955–67. (PMID: 337911667994158) |
| معلومات مُعتمدة: | MC_UU_00008/10 United Kingdom MRC_ Medical Research Council; MC_UU_00036/4 United Kingdom MRC_ Medical Research Council |
| المشرفين على المادة: | 0 (NF-E2-Related Factor 2) 0 (Nfe2l2 protein, mouse) |
| تواريخ الأحداث: | Date Created: 20231019 Date Completed: 20240112 Latest Revision: 20240627 |
| رمز التحديث: | 20240628 |
| DOI: | 10.1038/s41375-023-02067-9 |
| PMID: | 37857886 |
| قاعدة البيانات: | MEDLINE |
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Full Text Finder | تدمد: | 1476-5551 |
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| DOI: | 10.1038/s41375-023-02067-9 |