ONCOGENE：健康所白血病细胞分化最新研究进展

生物谷

健康科学研究所陈国强研究组一直致力于白血病细胞分化和凋亡的分子机制和治疗学基础研究，取得系列重要发现。继发现低氧可以诱导白血病细胞分化并伴随低氧诱导因子HIF-1α蛋白累积之后，最近，为了深入探索低氧诱导分化的分子机制、明确HIF-1α蛋白在分化中的作用，他们建立了受四环素可控诱导表达HIF-1α的急性髓系白血病细胞系，通过对分化指标的检测分析，结果发现，HIF-1α蛋白的累积可直接引起白血病细胞向中性粒细胞分化成熟。与此对应地，当采用RNAi技术特异性抑制HIF-1α的表达后，低氧及其模拟化合物诱导的分化也受到了显著的抑制。在此基础上，他们还通过干扰HIF-1α、C/EBP等相关基因的表达，发现HIF-1α引起的白血病细胞分化并不依赖其自身的转录因子活性，而是通过与粒系分化相关的转录因子C/EBP相互作用，并以此增强后者转录活性，从而实现细胞的粒系成熟的。这些发现不仅对于深入认识造血细胞分化和白血病发病的分子机制具有重要科学价值，也为诱导分化治疗模式在其它类型白血病的突破奠定了重要的实验基础。相关内容已发表在ONCOGENE上。

原始出处:

Oncogene advance online publication 6 August 2007; doi: 10.1038/sj.onc.1210676

Physical and functional interaction of Runt-related protein 1 with hypoxia-inducible factor-1

Z G Peng1,4, M Y Zhou1,4, Y Huang2,3, J H Qiu3, L S Wang2, S H Liao1, S Dong3 and G Q Chen1,2

1Institute of Health Science, Shanghai Institutes for Biological Sciences of Chinese Academy of Sciences-Shanghai Jiao-Tong University School of Medicine (SJTU-SM, formerly Shanghai Second Medical University), Shanghai, China
2Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, SJTU-SM, Shanghai, China
3Department of Medicine, Baylor College of Medicine, Houston, TX, USA

Correspondence: Professsor G-Q Chen, Department of Pathophysiology, Shanghai Jiaotong University School of Medicine, No. 280, Chong-Qing South Road, Shanghai 200025, China. E-mail: chengq@shsmu.edu.cn or gqchen@sibs.ac.cn

4These two authors contributed equally to this work.

Received 30 December 2006; Revised 23 April 2007; Accepted 18 June 2007; Published online 6 August 2007.

Angiogenesis and hematopoiesis are closely linked and interactive with each other, but few studies were given to identify possible links between angiogenesis-promoting proteins and hematopoiesis-related transcription factors. Here we investigated the potential relationship of oxygen-sensitive -subunit of angiogenesis-related hypoxia-inducible factor-1 (HIF-1) with Runt-related protein 1 (Runx1, also known as acute myeloid leukemia-1, AML-1), an important hematopoietic transcription factor. The results demonstrated that Runx1 and HIF-1 proteins directly interacted with each other to a degree, in which Runt homology domain of Runx1 was mainly involved. Leukemia-related abnormal Runx1 fusion protein AML1-ETO, which fuses the N-terminal 177 amino acid residues of the Runx1 protein in frame to ETO (eight-twenty-one) protein, also interacted with HIF-1 protein with greater ability than Runx1 itself. More intriguingly, Runx1 overexpression inhibited DNA-binding and transcriptional activity of HIF-1 protein with reduced expression of HIF-1-targeted genes such as vascular endothelial growth factor, while silence of Runx1 expression by specific small interfering RNA significantly increased transcriptional activity of HIF-1 protein, suggesting that Runx1 inhibited transcription-dependent function of HIF-1. Vice versa, HIF-1 increased DNA-binding ability and transcriptional activity of Runx1 protein. All these data would shed new insight to understanding Runx1 and HIF-1-related hematopoietic cell differentiation and angiogenesis.