RUNX1 haploinsufficiency results in granulocyte colony-stimulating factor hypersensitivity.
RUNX1 haploinsufficiency results in granulocyte colony-stimulating factor hypersensitivity.
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DOI：
10.1038/bcj.2015.105
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发表时间：
2016-01-08
影响因子：
12.8
通讯作者：
Osato M
中科院分区：
文献类型：
--
作者：
Chin DW;Sakurai M;Nah GS;Du L;Jacob B;Yokomizo T;Matsumura T;Suda T;Huang G;Fu XY;Ito Y;Nakajima H;Osato M
RUNX 1/AML 1是人类白血病中最常见的突变基因之一。RUNX 1的单倍不足导致家族性血小板疾病，具有骨髓恶性肿瘤（FPD/MM）的易感性。然而，FPD/MM的分子机制仍不清楚。在这里，我们表明，小鼠Runx 1 +/−造血细胞对粒细胞集落刺激因子（G-CSF）高度敏感，导致干/祖细胞的扩增和动员增强，骨髓分化阻滞。在G-CSF刺激后，Runx 1 +/−细胞与Runx 1 +/+细胞相比表现出更明显的STAT 3磷酸化，这可能是由于减少了Pias 3（STAT 3信号传导的关键负调节因子）的表达，以及减少了RUNX 1对STAT 3的物理隔离。最重要的是，患有RUNX 1突变的FPD患者的血细胞表现出类似的G-CSF超敏反应。总之，Runx 1单倍不足似乎通过扩增干/祖细胞库和阻断对G-CSF应答的骨髓分化而使FPD患者易患MM。
RUNX1/AML1 is among the most commonly mutated genes in human leukemia. Haploinsufficiency of RUNX1 causes familial platelet disorder with predisposition to myeloid malignancies (FPD/MM). However, the molecular mechanism of FPD/MM remains unknown. Here we show that murine Runx1+/− hematopoietic cells are hypersensitive to granulocyte colony-stimulating factor (G-CSF), leading to enhanced expansion and mobilization of stem/progenitor cells and myeloid differentiation block. Upon G-CSF stimulation, Runx1+/− cells exhibited a more pronounced phosphorylation of STAT3 as compared with Runx1+/+ cells, which may be due to reduced expression of Pias3, a key negative regulator of STAT3 signaling, and reduced physical sequestration of STAT3 by RUNX1. Most importantly, blood cells from a FPD patient with RUNX1 mutation exhibited similar G-CSF hypersensitivity. Taken together, Runx1 haploinsufficiency appears to predispose FPD patients to MM by expanding the pool of stem/progenitor cells and blocking myeloid differentiation in response to G-CSF.