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Herein, single-cell interrogation found Flt3 mRNA expression to be absent in the large majority of phenotypic HSCs, with a strong negative correlation between Flt3 and HSC-associated gene expression. Flt3-ITD knock-in mice showed reduced numbers of phenotypic HSCs, with an even more severe loss of long-term repopulating HSCs, likely reflecting the presence of non-HSCs within the phenotypic HSC compartment. Competitive transplantation experiments established that Flt3-ITD compromises HSCs through an extrinsically mediated mechanism of disrupting HSC-supporting bone marrow stromal cells, with reduced numbers of endothelial and mesenchymal stromal cells showing increased inflammation-associated gene expression. Tumor necrosis factor (TNF), a cell-extrinsic potent negative regulator of HSCs, was overexpressed in bone marrow niche cells from FLT3-ITD mice, and anti-TNF treatment partially rescued the HSC phenotype. These findings, which establish that Flt3-ITD\u2013driven myeloproliferation results in cell-extrinsic suppression of the normal HSC reservoir, are of relevance for several aspects of acute myeloid leukemia biology.<\/jats:p>","DOI":"10.1084\/jem.20161418","type":"journal-article","created":{"date-parts":[[2017,6,21]],"date-time":"2017-06-21T14:10:48Z","timestamp":1498054248000},"page":"2005-2021","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":46,"title":["Niche-mediated depletion of the normal hematopoietic stem cell reservoir by Flt3-ITD\u2013induced myeloproliferation"],"prefix":"10.1084","volume":"214","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8522-1002","authenticated-orcid":true,"given":"Adam J.","family":"Mead","sequence":"first","affiliation":[{"name":"Haematopoietic Stem Cell Biology Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK 1"},{"name":"Medical Research 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