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dc.contributorVall d'Hebron Barcelona Hospital Campus
dc.contributor.authorCasado, Jose A
dc.contributor.authorValeri, Antonio
dc.contributor.authorSánchez-Domínguez, Rebeca
dc.contributor.authorVela Cristobal, Paula
dc.contributor.authorLópez, Andrea
dc.contributor.authorNavarro, Susana
dc.contributor.authorDíaz de Heredia Rubio, Maria Cristina
dc.date.accessioned2022-09-09T12:50:57Z
dc.date.available2022-09-09T12:50:57Z
dc.date.issued2022-08-01
dc.identifier.citationCasado JA, Valeri A, Sanchez-Domínguez R, Vela P, López A, Navarro S, et al. Upregulation of NKG2D ligands impairs hematopoietic stem cell function in Fanconi anemia. J Clin Invest. 2022 Aug 1;132(15):e142842.
dc.identifier.issn1558-8238
dc.identifier.urihttp://hdl.handle.net/11351/8119
dc.descriptionCellular immune response; Immunology; Stem cells
dc.description.abstractFanconi 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.
dc.language.isoeng
dc.publisherAmerican Society for Clinical Investigation
dc.relation.ispartofseriesThe Journal of Clinical Investigation;132(15)
dc.rightsAttribution 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.sourceScientia
dc.subjectAnèmia de Fanconi
dc.subjectCèl·lules mare hematopoètiques
dc.subjectRegulació genètica
dc.subject.meshFanconi Anemia
dc.subject.meshHematopoietic Stem Cells
dc.subject.meshUp-Regulation
dc.titleUpregulation of NKG2D ligands impairs hematopoietic stem cell function in Fanconi anemia
dc.typeinfo:eu-repo/semantics/article
dc.identifier.doi10.1172/JCI142842
dc.subject.decsanemia de Fanconi
dc.subject.decscélulas madre hematopoyéticas
dc.subject.decsregulación positiva
dc.relation.publishversionhttp://dx.doi.org/10.1172/JCI142842
dc.type.versioninfo:eu-repo/semantics/publishedVersion
dc.audienceProfessionals
dc.contributor.organismesInstitut Català de la Salut
dc.contributor.authoraffiliation[Casado JA, Valeri A, Sanchez-Domínguez R, Vela P, López A, Navarro S] Division of Innovative Therapies, CIEMAT and Advanced Therapies Unit, IIS-Fundación Jimenez Diaz and Autónoma University, Madrid, Spain. Biomedical Center for Research on Rare Diseases (CIBERER), Madrid, Spain. [Díaz de Heredia C] Servei d’Oncologia i Hematologia Pediàtriques, Vall d’Hebron Hospital Universitari, Barcelona, Spain
dc.identifier.pmid35671096
dc.identifier.wos000842455700003
dc.rights.accessrightsinfo:eu-repo/semantics/openAccess


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