Niche-mediated depletion of the normal hematopoietic stem cell reservoir by Flt3-ITD-induced myeloproliferation.
Adam J MeadWen Hao NeoNikolaos BarkasSahoko MatsuokaAlice GiustacchiniRaffaella FacchiniSupat ThongjueaLauren JamiesonChristopher A G BoothNicholas J FordhamCristina Di GenuaDeborah AtkinsonOnima ChowdhuryEmmanouela RepapiNicki GrayShabnam KharaziSally-Ann ClarkTiphaine BouriezPetter S WollToshio SudaClaus NerlovSten Eirik W JacobsenPublished in: The Journal of experimental medicine (2017)
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.
Keyphrases
- acute myeloid leukemia
- tyrosine kinase
- bone marrow
- allogeneic hematopoietic stem cell transplantation
- gene expression
- single cell
- stem cells
- rheumatoid arthritis
- epidermal growth factor receptor
- cell therapy
- mesenchymal stem cells
- dna methylation
- poor prognosis
- endothelial cells
- oxidative stress
- rna seq
- high throughput
- insulin resistance
- adipose tissue
- skeletal muscle