文章：

RUNX1单倍剂量不足导致粒细胞集落刺激因子高敏反应

RUNX1 haploinsufficiency results in granulocyte colony-stimulating factor hypersensitivity

原文发布日期：2016-01-08

DOI: 10.1038/bcj.2015.105

类型: Original Article

开放获取: 是

英文摘要：

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.

摘要翻译： 

RUNX1/AML1是人类白血病中最常发生突变的基因之一。RUNX1单倍体不足会导致易患髓系恶性肿瘤的家族性血小板病（FPD/MM）。然而，FPD/MM的分子机制仍不明确。本研究发现，小鼠Runx1+/−造血细胞对粒细胞集落刺激因子（G-CSF）表现出超敏反应，导致干细胞/祖细胞扩增和动员增强，并出现髓系分化阻滞。在G-CSF刺激下，与Runx1+/+细胞相比，Runx1+/−细胞表现出更显著的STAT3磷酸化，这可能是由于STAT3信号通路关键负调控因子Pias3表达降低，以及RUNX1对STAT3的物理隔离作用减弱所致。最重要的是，一名携带RUNX1突变的FPD患者外周血细胞同样表现出G-CSF超敏反应。综上所述，Runx1单倍体不足可能通过扩大干细胞/祖细胞库并阻断G-CSF诱导的髓系分化，使FPD患者易感髓系恶性肿瘤。

原文链接：

RUNX1 haploinsufficiency results in granulocyte colony-stimulating factor hypersensitivity