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ResearchIn-Press PreviewImmunologyStem cells Open Access | 10.1172/JCI142842

Upregulation of NKG2D ligands impairs hematopoietic stem cell function in Fanconi anemia

Jose A. Casado,1 Antonio Valeri,1 Rebeca Sanchez-Domínguez,1 Paula Vela,1 Andrea Lopez,1 Susana Navarro,1 Omaira Alberquilla,1 Helmut Hanenberg,2 Roser Pujol,3 Jose C. Segovia,1 Jordi Minguillón,3 Jordi Surrallés,3 Cristina Diaz-de-Heredia,4 Julián Sevilla,4 Paula Rio,1 and Juan A. Bueren1

1Division of Innovative Therapies, CIEMAT and Advanced Therapies Unit, IIS-Fundación Jimenez Diaz and Autónoma University, Madrid, Spain

2Department of Pediatrics, University Hospital, University Duisburg-Essen, Essen, Germany

3Department of Genetics and Microbiology, Universitat Autónoma de Barcelona, Barcelona, Spain

4Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca, Barcelona, Spain

5Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca, Madrid, Spain

Find articles by Casado, J. in: JCI | PubMed | Google Scholar

1Division of Innovative Therapies, CIEMAT and Advanced Therapies Unit, IIS-Fundación Jimenez Diaz and Autónoma University, Madrid, Spain

2Department of Pediatrics, University Hospital, University Duisburg-Essen, Essen, Germany

3Department of Genetics and Microbiology, Universitat Autónoma de Barcelona, Barcelona, Spain

4Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca, Barcelona, Spain

5Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca, Madrid, Spain

Find articles by Valeri, A. in: JCI | PubMed | Google Scholar

1Division of Innovative Therapies, CIEMAT and Advanced Therapies Unit, IIS-Fundación Jimenez Diaz and Autónoma University, Madrid, Spain

2Department of Pediatrics, University Hospital, University Duisburg-Essen, Essen, Germany

3Department of Genetics and Microbiology, Universitat Autónoma de Barcelona, Barcelona, Spain

4Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca, Barcelona, Spain

5Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca, Madrid, Spain

Find articles by Sanchez-Domínguez, R. in: JCI | PubMed | Google Scholar

1Division of Innovative Therapies, CIEMAT and Advanced Therapies Unit, IIS-Fundación Jimenez Diaz and Autónoma University, Madrid, Spain

2Department of Pediatrics, University Hospital, University Duisburg-Essen, Essen, Germany

3Department of Genetics and Microbiology, Universitat Autónoma de Barcelona, Barcelona, Spain

4Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca, Barcelona, Spain

5Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca, Madrid, Spain

Find articles by Vela, P. in: JCI | PubMed | Google Scholar |

1Division of Innovative Therapies, CIEMAT and Advanced Therapies Unit, IIS-Fundación Jimenez Diaz and Autónoma University, Madrid, Spain

2Department of Pediatrics, University Hospital, University Duisburg-Essen, Essen, Germany

3Department of Genetics and Microbiology, Universitat Autónoma de Barcelona, Barcelona, Spain

4Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca, Barcelona, Spain

5Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca, Madrid, Spain

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1Division of Innovative Therapies, CIEMAT and Advanced Therapies Unit, IIS-Fundación Jimenez Diaz and Autónoma University, Madrid, Spain

2Department of Pediatrics, University Hospital, University Duisburg-Essen, Essen, Germany

3Department of Genetics and Microbiology, Universitat Autónoma de Barcelona, Barcelona, Spain

4Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca, Barcelona, Spain

5Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca, Madrid, Spain

Find articles by Navarro, S. in: JCI | PubMed | Google Scholar

1Division of Innovative Therapies, CIEMAT and Advanced Therapies Unit, IIS-Fundación Jimenez Diaz and Autónoma University, Madrid, Spain

2Department of Pediatrics, University Hospital, University Duisburg-Essen, Essen, Germany

3Department of Genetics and Microbiology, Universitat Autónoma de Barcelona, Barcelona, Spain

4Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca, Barcelona, Spain

5Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca, Madrid, Spain

Find articles by Alberquilla, O. in: JCI | PubMed | Google Scholar

1Division of Innovative Therapies, CIEMAT and Advanced Therapies Unit, IIS-Fundación Jimenez Diaz and Autónoma University, Madrid, Spain

2Department of Pediatrics, University Hospital, University Duisburg-Essen, Essen, Germany

3Department of Genetics and Microbiology, Universitat Autónoma de Barcelona, Barcelona, Spain

4Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca, Barcelona, Spain

5Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca, Madrid, Spain

Find articles by Hanenberg, H. in: JCI | PubMed | Google Scholar

1Division of Innovative Therapies, CIEMAT and Advanced Therapies Unit, IIS-Fundación Jimenez Diaz and Autónoma University, Madrid, Spain

2Department of Pediatrics, University Hospital, University Duisburg-Essen, Essen, Germany

3Department of Genetics and Microbiology, Universitat Autónoma de Barcelona, Barcelona, Spain

4Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca, Barcelona, Spain

5Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca, Madrid, Spain

Find articles by Pujol, R. in: JCI | PubMed | Google Scholar

1Division of Innovative Therapies, CIEMAT and Advanced Therapies Unit, IIS-Fundación Jimenez Diaz and Autónoma University, Madrid, Spain

2Department of Pediatrics, University Hospital, University Duisburg-Essen, Essen, Germany

3Department of Genetics and Microbiology, Universitat Autónoma de Barcelona, Barcelona, Spain

4Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca, Barcelona, Spain

5Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca, Madrid, Spain

Find articles by Segovia, J. in: JCI | PubMed | Google Scholar |

1Division of Innovative Therapies, CIEMAT and Advanced Therapies Unit, IIS-Fundación Jimenez Diaz and Autónoma University, Madrid, Spain

2Department of Pediatrics, University Hospital, University Duisburg-Essen, Essen, Germany

3Department of Genetics and Microbiology, Universitat Autónoma de Barcelona, Barcelona, Spain

4Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca, Barcelona, Spain

5Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca, Madrid, Spain

Find articles by Minguillón, J. in: JCI | PubMed | Google Scholar

1Division of Innovative Therapies, CIEMAT and Advanced Therapies Unit, IIS-Fundación Jimenez Diaz and Autónoma University, Madrid, Spain

2Department of Pediatrics, University Hospital, University Duisburg-Essen, Essen, Germany

3Department of Genetics and Microbiology, Universitat Autónoma de Barcelona, Barcelona, Spain

4Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca, Barcelona, Spain

5Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca, Madrid, Spain

Find articles by Surrallés, J. in: JCI | PubMed | Google Scholar

1Division of Innovative Therapies, CIEMAT and Advanced Therapies Unit, IIS-Fundación Jimenez Diaz and Autónoma University, Madrid, Spain

2Department of Pediatrics, University Hospital, University Duisburg-Essen, Essen, Germany

3Department of Genetics and Microbiology, Universitat Autónoma de Barcelona, Barcelona, Spain

4Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca, Barcelona, Spain

5Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca, Madrid, Spain

Find articles by Diaz-de-Heredia, C. in: JCI | PubMed | Google Scholar |

1Division of Innovative Therapies, CIEMAT and Advanced Therapies Unit, IIS-Fundación Jimenez Diaz and Autónoma University, Madrid, Spain

2Department of Pediatrics, University Hospital, University Duisburg-Essen, Essen, Germany

3Department of Genetics and Microbiology, Universitat Autónoma de Barcelona, Barcelona, Spain

4Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca, Barcelona, Spain

5Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca, Madrid, Spain

Find articles by Sevilla, J. in: JCI | PubMed | Google Scholar |

1Division of Innovative Therapies, CIEMAT and Advanced Therapies Unit, IIS-Fundación Jimenez Diaz and Autónoma University, Madrid, Spain

2Department of Pediatrics, University Hospital, University Duisburg-Essen, Essen, Germany

3Department of Genetics and Microbiology, Universitat Autónoma de Barcelona, Barcelona, Spain

4Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca, Barcelona, Spain

5Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca, Madrid, Spain

Find articles by Rio, P. in: JCI | PubMed | Google Scholar

1Division of Innovative Therapies, CIEMAT and Advanced Therapies Unit, IIS-Fundación Jimenez Diaz and Autónoma University, Madrid, Spain

2Department of Pediatrics, University Hospital, University Duisburg-Essen, Essen, Germany

3Department of Genetics and Microbiology, Universitat Autónoma de Barcelona, Barcelona, Spain

4Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca, Barcelona, Spain

5Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca, Madrid, Spain

Find articles by Bueren, J. in: JCI | PubMed | Google Scholar

Published June 7, 2022 - More info

J Clin Invest. https://doi.org/10.1172/JCI142842.
Copyright © 2022, Casado et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published June 7, 2022 - Version history
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Abstract

Fanconi Anemia (FA) is the most prevalent inherited bone marrow failure (BMF) syndrome. Nevertheless, the pathophysiological mechanisms of BMF in FA have not been fully elucidated. Since FA cells are defective in DNA repair, we hypothesized that FA hematopoietic stem and progenitor cells (HSPCs) might express DNA damage-associated stress molecules such as Natural Killer group 2 member D ligands (NKG2D-Ls). These ligands could then interact with the activating NKG2D receptor expressed in cytotoxic NK or CD8+ T cells which may result in progressive HSPCs depletion. Our results indeed demonstrated upregulated levels of NKG2D-Ls in cultured FA fibroblasts and T cells, which were further exacerbated by mitomycin C or formaldehyde. Notably, a high proportion of BM CD34+ HSPCs from FA patients also expressed increased levels of NKG2D-Ls, which correlated inversely with the percentage of CD34+ cells in BM. Remarkably, the reduced clonogenic potential characteristic of FA HSPCs was improved by blocking NKG2D/NKG2D-L interactions. Moreover, the in vivo blockage of these interactions in a BMF FA mouse model ameliorated the anemia in these animals. Our study demonstrates the involvement of NKG2D/NKG2D-L interactions in FA HSPC functionality, suggesting an unexpected role of the immune system in the progressive BMF characteristic of FA.

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