{"entity": "publication", "iuid": "c39c34f5c43d412487543502873a6519", "timestamp": "2026-08-10T22:42:19.087Z", "links": {"self": {"href": "https://publications.scilifelab.se/publication/c39c34f5c43d412487543502873a6519.json"}, "display": {"href": "https://publications.scilifelab.se/publication/c39c34f5c43d412487543502873a6519"}}, "title": "Niche-mediated depletion of the normal hematopoietic stem cell reservoir by Flt3-ITD-induced myeloproliferation.", "authors": [{"family": "Mead", "given": "Adam J", "initials": "AJ"}, {"family": "Neo", "given": "Wen Hao", "initials": "WH"}, {"family": "Barkas", "given": "Nikolaos", "initials": "N"}, {"family": "Matsuoka", "given": "Sahoko", "initials": "S"}, {"family": "Giustacchini", "given": "Alice", "initials": "A"}, {"family": "Facchini", "given": "Raffaella", "initials": "R"}, {"family": "Thongjuea", "given": "Supat", "initials": "S"}, {"family": "Jamieson", "given": "Lauren", "initials": "L"}, {"family": "Booth", "given": "Christopher A G", "initials": "CAG"}, {"family": "Fordham", "given": "Nicholas", "initials": "N"}, {"family": "Di Genua", "given": "Cristina", "initials": "C"}, {"family": "Atkinson", "given": "Deborah", "initials": "D"}, {"family": "Chowdhury", "given": "Onima", "initials": "O"}, {"family": "Repapi", "given": "Emmanouela", "initials": "E"}, {"family": "Gray", "given": "Nicki", "initials": "N"}, {"family": "Kharazi", "given": "Shabnam", "initials": "S"}, {"family": "Clark", "given": "Sally-Ann", "initials": "SA"}, {"family": "Bouriez", "given": "Tiphaine", "initials": "T"}, {"family": "Woll", "given": "Petter", "initials": "P"}, {"family": "Suda", "given": "Toshio", "initials": "T"}, {"family": "Nerlov", "given": "Claus", "initials": "C"}, {"family": "Jacobsen", "given": "Sten Eirik W", "initials": "SEW"}], "type": "journal article", "published": "2017-07-03", "journal": {"volume": "214", "issn": "1540-9538", "issue": "7", "pages": "2005-2021", "title": "J. Exp. Med.", "issn-l": "0022-1007"}, "abstract": "Although previous studies suggested that the expression of FMS-like tyrosine kinase 3 (Flt3) initiates downstream of mouse hematopoietic stem cells (HSCs), FLT3 internal tandem duplications (FLT3 ITDs) have recently been suggested to intrinsically suppress HSCs. 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-driven myeloproliferation results in cell-extrinsic suppression of the normal HSC reservoir, are of relevance for several aspects of acute myeloid leukemia biology.", "doi": "10.1084/jem.20161418", "pmid": "28637883", "labels": {"National Genomics Infrastructure": "Service", "NGI Stockholm (Genomics Applications)": "Service", "NGI Stockholm (Genomics Production)": "Service"}, "xrefs": [{"db": "pii", "key": "jem.20161418"}, {"db": "pmc", "key": "PMC5502426"}], "notes": [], "created": "2018-01-10T09:44:12.302Z", "modified": "2020-01-21T13:56:10.871Z"}