The Finsen Laboratory/Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.
Leukemia. 2016 Apr;30(4):767-75. doi: 10.1038/leu.2015.324. Epub 2015 Nov 25.
The process of blood formation, haematopoiesis, depends upon a small number of haematopoietic stem cells (HSCs) that reside in the bone marrow. Differentiation of HSCs is characterised by decreased expression of genes associated with self-renewal accompanied by a stepwise activation of genes promoting differentiation. Lineage branching is further directed by groups of cooperating and counteracting genes forming complex networks of lineage-specific transcription factors. Imbalances in such networks can result in blockage of differentiation, lineage reprogramming and malignant transformation. CCAAT/enhancer-binding protein-α (C/EBPα) was originally identified 30 years ago as a transcription factor that binds both promoter and enhancer regions. Most of the early work focused on the role of C/EBPα in regulating transcriptional processes as well as on its functions in key differentiation processes during liver, adipogenic and haematopoietic development. Specifically, C/EBPα was shown to control differentiation by its ability to coordinate transcriptional output with cell cycle progression. Later, its role as an important tumour suppressor, mainly in acute myeloid leukaemia (AML), was recognised and has been the focus of intense studies by a number of investigators. More recent work has revisited the role of C/EBPα in normal haematopoiesis, especially its function in HSCs, and also started to provide more mechanistic insights into its role in normal and malignant haematopoiesis. In particular, the differential actions of C/EBPα isoforms, as well as its importance in chromatin remodelling and cellular reprogramming, are beginning to be elucidated. Finally, recent work has also shed light on the dichotomous function of C/EBPα in AML by demonstrating its ability to act as both a tumour suppressor and promoter. In the present review, we will summarise the current knowledge on the functions of C/EBPα during normal and malignant haematopoiesis with special emphasis on the recent work.
血液形成的过程，造血，依赖于少量驻留在骨髓中的造血干细胞（HSCs）。HSCs 的分化特征是与自我更新相关的基因表达减少，同时逐步激活促进分化的基因。谱系分支进一步由协同和拮抗的基因群指导，形成具有谱系特异性转录因子的复杂网络。这些网络的失衡可能导致分化受阻、谱系重编程和恶性转化。CCAAT/增强子结合蛋白-α（C/EBPα）最初是在 30 年前作为一种转录因子被鉴定出来的，它可以结合启动子和增强子区域。早期的大部分工作都集中在 C/EBPα 在调节转录过程中的作用以及在肝脏、脂肪生成和造血发育过程中的关键分化过程中的作用。具体而言，C/EBPα 通过协调转录输出与细胞周期进程的能力来控制分化。后来，人们认识到它作为一种重要的肿瘤抑制因子，主要在急性髓系白血病（AML）中，它的作用一直是许多研究人员研究的重点。最近的工作重新审视了 C/EBPα 在正常造血中的作用，特别是它在 HSCs 中的功能，并且开始提供更多关于其在正常和恶性造血中的作用的机制见解。特别是，C/EBPα 同工型的差异作用，以及它在染色质重塑和细胞重编程中的重要性，开始被阐明。最后，最近的工作还通过证明 C/EBPα 既能作为肿瘤抑制因子又能作为肿瘤促进因子的能力，揭示了 C/EBPα 在 AML 中的二分功能。在本综述中，我们将总结 C/EBPα 在正常和恶性造血中的功能的最新知识，特别强调最近的工作。
