Niche-mediated depletion of the normal hematopoietic stem cell reservoir by Flt3-ITD–induced myeloproliferation
Autor: | Mead, Adam J., Neo, Wen Hao, Barkas, Nikolaos, Matsuoka, Sahoko, Giustacchini, Alice, Facchini, Raffaella, Thongjuea, Supat, Jamieson, Lauren, Booth, Christopher A.G., Fordham, Nicholas, Di Genua, Cristina, Atkinson, Deborah, Chowdhury, Onima, Repapi, Emmanouela, Gray, Nicki, Kharazi, Shabnam, Clark, Sally-Ann, Bouriez, Tiphaine, Woll, Petter, Suda, Toshio, Nerlov, Claus, Jacobsen, Sten Eirik W. |
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Jazyk: | angličtina |
Rok vydání: | 2017 |
Předmět: |
Bone Marrow Cells
Mice Transgenic Article Etanercept fluids and secretions hemic and lymphatic diseases Animals Stem Cell Niche Research Articles Cells Cultured Bone Marrow Transplantation Cell Proliferation Reverse Transcriptase Polymerase Chain Reaction Tumor Necrosis Factor-alpha Gene Expression Profiling Anti-Inflammatory Agents Non-Steroidal hemic and immune systems Mesenchymal Stem Cells Hematopoietic Stem Cells Mice Inbred C57BL fms-Like Tyrosine Kinase 3 Tandem Repeat Sequences embryonic structures Mutation Single-Cell Analysis |
Zdroj: | The Journal of Experimental Medicine |
ISSN: | 1540-9538 0022-1007 |
Popis: | Flt3 expression is absent in the large majority of phenotypic hematopoietic stem cells (HSCs). Mead et al. show that FLT3-ITD–driven myeloproliferation causes cell-extrinsic suppression of the normal HSC reservoir through disruption of HSC-supporting BM stromal cells, including overexpression of TNF. 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. |
Databáze: | OpenAIRE |
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