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dc.contributor.authorWaclawiczek, A
dc.contributor.authorHamilton, A
dc.contributor.authorRouault-Pierre, K
dc.contributor.authorAbarrategi, A
dc.contributor.authorAlbornoz, MG
dc.contributor.authorMiraki-Moud, F
dc.contributor.authorBah, N
dc.contributor.authorGribben, J
dc.contributor.authorFitzgibbon, J
dc.contributor.authorTaussig, D
dc.contributor.authorBonnet, D
dc.date.accessioned2022-05-09T14:47:43Z
dc.date.available2022-05-09T14:47:43Z
dc.identifier.citationThe Journal of clinical investigation, 2020, 130 (6), pp. 3038 - 3050en
dc.identifier.issn0021-9738
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/5117
dc.identifier.eissn1558-8238en_US
dc.identifier.eissn1558-8238
dc.identifier.doi10.1172/jci133187en_US
dc.identifier.doi10.1172/jci133187
dc.description.abstractAcute myeloid leukemia (AML) disrupts the generation of normal blood cells, predisposing patients to hemorrhage, anemia, and infections. Differentiation and proliferation of residual normal hematopoietic stem and progenitor cells (HSPCs) are impeded in AML-infiltrated bone marrow (BM). The underlying mechanisms and interactions of residual hematopoietic stem cells (HSCs) within the leukemic niche are poorly understood, especially in the human context. To mimic AML infiltration and dissect the cellular crosstalk in human BM, we established humanized ex vivo and in vivo niche models comprising AML cells, normal HSPCs, and mesenchymal stromal cells (MSCs). Both models replicated the suppression of phenotypically defined HSPC differentiation without affecting their viability. As occurs in AML patients, the majority of HSPCs were quiescent and showed enrichment of functional HSCs. HSPC suppression was largely dependent on secreted factors produced by transcriptionally remodeled MSCs. Secretome analysis and functional validation revealed MSC-derived stanniocalcin 1 (STC1) and its transcriptional regulator HIF-1α as limiting factors for HSPC proliferation. Abrogation of either STC1 or HIF-1α alleviated HSPC suppression by AML. This study provides a humanized model to study the crosstalk among HSPCs, leukemia, and their MSC niche, and a molecular mechanism whereby AML impairs normal hematopoiesis by remodeling the mesenchymal niche.en_US
dc.formatPrinten_US
dc.format.extent3038 - 3050en_US
dc.languageengen_US
dc.language.isoengen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectHematopoietic Stem Cellsen_US
dc.subjectHL-60 Cellsen_US
dc.subjectU937 Cellsen_US
dc.subjectMesenchymal Stem Cellsen_US
dc.subjectAnimalsen_US
dc.subjectMice, Inbred NODen_US
dc.subjectMice, Knockouten_US
dc.subjectHumansen_US
dc.subjectMiceen_US
dc.subjectMice, SCIDen_US
dc.subjectGlycoproteinsen_US
dc.subjectNeoplasm Proteinsen_US
dc.subjectHematopoiesisen_US
dc.subjectFemaleen_US
dc.subjectMaleen_US
dc.subjectHypoxia-Inducible Factor 1, alpha Subuniten_US
dc.subjectLeukemia, Myeloid, Acuteen_US
dc.titleMesenchymal niche remodeling impairs hematopoiesis via stanniocalcin 1 in acute myeloid leukemia.en
dc.typeJournal Article
dcterms.dateAccepted2020-02-26
rioxxterms.versionVoRen
rioxxterms.versionofrecord10.1172/jci133187en
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0en
dc.relation.isPartOfThe Journal of clinical investigationen_US
pubs.issue6en_US
pubs.notesNot knownen_US
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Acute Leukaemia
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Acute Leukaemia/Acute Leukaemia (hon.)
pubs.organisational-group/ICR/Primary Group/Royal Marsden Clinical Units
pubs.publication-statusPublisheden_US
pubs.volume130en_US
pubs.embargo.termsNot knownen_US
icr.researchteamAcute Leukaemia
dc.contributor.icrauthorTaussig, Daviden_US


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