Niche-mediated depletion of the normal hematopoietic stem cell reservoir by Flt3-ITD-induced myeloproliferation.
Niche-mediated depletion of the normal hematopoietic stem cell reservoir by Flt3-ITD-induced myeloproliferation.
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DOI：
10.1084/jem.20161418
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发表时间：
2017-07-03
期刊：
影响因子：
--
通讯作者：
Jacobsen SEW
中科院分区：
文献类型：
--
作者：
Mead AJ;Neo WH;Barkas N;Matsuoka S;Giustacchini A;Facchini R;Thongjuea S;Jamieson L;Booth CAG;Fordham N;Di Genua C;Atkinson D;Chowdhury O;Repapi E;Gray N;Kharazi S;Clark SA;Bouriez T;Woll P;Suda T;Nerlov C;Jacobsen SEW
绝大多数表型造血干细胞(HSCs)不表达Flt3。Mead等人。研究表明，Flt3-ITD驱动的骨髓增殖通过破坏支持HSC的骨髓基质细胞，包括肿瘤坏死因子的过度表达，导致正常HSC库的细胞外源性抑制。尽管先前的研究表明FMS样酪氨酸激酶3(Flt3)的表达始于小鼠造血干细胞(HSCs)的下游，但最近发现Flt3的内部串联复制(Flt3ITD)本质上抑制了HSCs。在此，单细胞询问发现，在绝大多数表型的HSC中，Flt3的mRNA表达缺失，并且Flt3与HSC相关基因的表达呈强烈的负相关。Flt3-ITD基因敲入小鼠的表型HSC数量减少，长期重新填充的HSC的丢失甚至更严重，这可能反映了表型HSC间存在非HSCs。竞争性移植实验证实，Flt3-ITD通过破坏支持HSC的骨髓基质细胞的外源性机制损害HSCs，内皮细胞和间充质基质细胞数量减少，炎症相关基因表达增加。肿瘤坏死因子(TNF)是HSC的细胞外源性强负调控因子，在Flt3-ITD小鼠的骨髓巢细胞中过表达，抗肿瘤坏死因子治疗部分挽救了HSC的表型。这些发现表明，Flt3-ITD驱动的骨髓增殖导致正常HSC库的细胞外源性抑制，这些发现与急性髓系白血病生物学的几个方面有关。
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.
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DOI：
10.1038/nri3062
发表时间：
2011-09-09
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
影响因子：
64.5
作者：
Adolfsson, J;Månsson, R;Jacobsen, SEW
通讯作者：
Jacobsen, SEW
影响因子：
20.3
作者：
Levis, M;Murphy, KM;Small, D
通讯作者：
Small, D
影响因子：
20.3
作者：
Kharazi, Shabnam;Mead, Adam J.;Jacobsen, Sten Eirik W.
通讯作者：
Jacobsen, Sten Eirik W.
影响因子：
50.3
作者：
Goardon, Nicolas;Marchi, Emanuele;Vyas, Paresh
通讯作者：
Vyas, Paresh