Upregulation of NKG2D ligands impairs hematopoietic stem cell function in Fanconi anemia
Por:
Casado, JA, Valeri, A, Sanchez-Dominguez, R, Vela, P, Lopez, A, Navarro, S, Alberquilla, O, Hanenberg, H, Pujol, R, Segovia, JC, Minguillon, J, Surralles, J, de Heredia, CD, Sevilla, J, Rio, P, Bueren, JA
Publicada:
1 ago 2022
Resumen:
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 HSPC depletion. Our results indeed demonstrated upregulated levels of NKG2D-Ls in cultured FA fibroblasts and T cells, and these levels were further exacerbated by mitomycin C or formaldehyde. Notably, a high proportion of BM CD34(+) HSPCs from patients with FA 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 that is characteristic of FA.
Filiaciones:
Casado, JA:
IIS Fdn Jimenez Diaz, Div Innovat Therapies, CIEMAT, Madrid, Spain
IIS Fdn Jimenez Diaz, Adv Therapies Unit, Madrid, Spain
Univ Autonoma Madrid, Madrid, Spain
Biomed Ctr Res Rare Dis CIBERER, Madrid, Spain
Valeri, A:
IIS Fdn Jimenez Diaz, Div Innovat Therapies, CIEMAT, Madrid, Spain
IIS Fdn Jimenez Diaz, Adv Therapies Unit, Madrid, Spain
Univ Autonoma Madrid, Madrid, Spain
Biomed Ctr Res Rare Dis CIBERER, Madrid, Spain
Sanchez-Dominguez, R:
IIS Fdn Jimenez Diaz, Div Innovat Therapies, CIEMAT, Madrid, Spain
IIS Fdn Jimenez Diaz, Adv Therapies Unit, Madrid, Spain
Univ Autonoma Madrid, Madrid, Spain
Biomed Ctr Res Rare Dis CIBERER, Madrid, Spain
Vela, P:
IIS Fdn Jimenez Diaz, Div Innovat Therapies, CIEMAT, Madrid, Spain
IIS Fdn Jimenez Diaz, Adv Therapies Unit, Madrid, Spain
Univ Autonoma Madrid, Madrid, Spain
Biomed Ctr Res Rare Dis CIBERER, Madrid, Spain
Lopez, A:
IIS Fdn Jimenez Diaz, Div Innovat Therapies, CIEMAT, Madrid, Spain
IIS Fdn Jimenez Diaz, Adv Therapies Unit, Madrid, Spain
Univ Autonoma Madrid, Madrid, Spain
Biomed Ctr Res Rare Dis CIBERER, Madrid, Spain
Navarro, S:
IIS Fdn Jimenez Diaz, Div Innovat Therapies, CIEMAT, Madrid, Spain
IIS Fdn Jimenez Diaz, Adv Therapies Unit, Madrid, Spain
Univ Autonoma Madrid, Madrid, Spain
Biomed Ctr Res Rare Dis CIBERER, Madrid, Spain
Alberquilla, O:
IIS Fdn Jimenez Diaz, Div Innovat Therapies, CIEMAT, Madrid, Spain
IIS Fdn Jimenez Diaz, Adv Therapies Unit, Madrid, Spain
Univ Autonoma Madrid, Madrid, Spain
Biomed Ctr Res Rare Dis CIBERER, Madrid, Spain
Hanenberg, H:
Univ Duisburg Essen, Dept Pediat 3, Univ Childrens Hosp Essen, Essen, Germany
Heinrich Heine Univ, Dept Otorhinolaryngol & Head & Neck Surg, Dusseldorf, Germany
Pujol, R:
Biomed Ctr Res Rare Dis CIBERER, Madrid, Spain
Univ Autonoma Barcelona, IIB St Pau, Hosp La Santa Reu & St Pau, Barcelona, Spain
Segovia, JC:
IIS Fdn Jimenez Diaz, Div Innovat Therapies, CIEMAT, Madrid, Spain
IIS Fdn Jimenez Diaz, Adv Therapies Unit, Madrid, Spain
Univ Autonoma Madrid, Madrid, Spain
Biomed Ctr Res Rare Dis CIBERER, Madrid, Spain
Minguillon, J:
Biomed Ctr Res Rare Dis CIBERER, Madrid, Spain
Univ Autonoma Barcelona, IIB St Pau, Hosp La Santa Reu & St Pau, Barcelona, Spain
Surralles, J:
Biomed Ctr Res Rare Dis CIBERER, Madrid, Spain
Univ Autonoma Barcelona, IIB St Pau, Hosp La Santa Reu & St Pau, Barcelona, Spain
de Heredia, CD:
Biomed Ctr Res Rare Dis CIBERER, Madrid, Spain
Hosp Univ Vall dHebron, Serv Oncol & Hematol Pediat, Barcelona, Spain
Sevilla, J:
Biomed Ctr Res Rare Dis CIBERER, Madrid, Spain
Hosp Nino Jesus, Stem Cell Transplant Unit, Madrid, Spain
Rio, P:
IIS Fdn Jimenez Diaz, Div Innovat Therapies, CIEMAT, Madrid, Spain
IIS Fdn Jimenez Diaz, Adv Therapies Unit, Madrid, Spain
Univ Autonoma Madrid, Madrid, Spain
Biomed Ctr Res Rare Dis CIBERER, Madrid, Spain
Bueren, JA:
IIS Fdn Jimenez Diaz, Div Innovat Therapies, CIEMAT, Madrid, Spain
IIS Fdn Jimenez Diaz, Adv Therapies Unit, Madrid, Spain
Univ Autonoma Madrid, Madrid, Spain
Biomed Ctr Res Rare Dis CIBERER, Madrid, Spain
gold, Green Published, All Open Access, Gold, Green
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