Chin D W L, Sakurai M, Nah G S S, Du L, Jacob B, Yokomizo T, Matsumura T, Suda T, Huang G, Fu X-Y, Ito Y, Nakajima H, Osato M
Cancer Science Institute of Singapore, National University of Singapore, Singapore.
Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
Blood Cancer J. 2016 Jan 8;6(1):e379. doi: 10.1038/bcj.2015.105.
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.
RUNX1/AML1是人类白血病中最常发生突变的基因之一。RUNX1单倍剂量不足会导致家族性血小板疾病并易患髓系恶性肿瘤（FPD/MM）。然而，FPD/MM的分子机制仍不清楚。在此我们表明，小鼠Runx1(+/-)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以及髓系分化阻滞。在G-CSF刺激下，与Runx1(+/+)细胞相比，Runx1(+/-)细胞表现出更明显的STAT3磷酸化，这可能是由于STAT3信号的关键负调节因子Pias3的表达降低，以及RUNX1对STAT3的物理隔离减少所致。最重要的是，一名患有RUNX1突变的FPD患者的血细胞表现出类似的G-CSF超敏反应。综上所述，Runx1单倍剂量不足似乎通过扩大干/祖细胞池并响应G-CSF阻断髓系分化，使FPD患者易患MM。
