文章：

造血和白血病的核心结合因子

Core-binding factors in haematopoiesis and leukaemia

原文发布日期：2002-07-01

DOI: 10.1038/nrc840

类型: Review Article

开放获取: 否

要点：

1. The heterodimeric transcription factor core-binding factors (CBFs) are comprised of the RUNX1 (also known as AML1, CBFA2 and PEBP2αB) and CBFβ subunits.
2. The RUNX1 subunit directly contacts DNA, and binding affinity for DNA is significantly increased by association with CBFβ, which does not contact DNA.
3. CBFs are involved in haematopoietic development. Knock-out mice indicate that both subunits of CBF are absolutely required for definitive haematopoiesis.
4. Correct CBF gene dosage is important during haematopoietic development. Subtle changes in the dosage of Runx1 can significantly affect the timing of stem-cell emergence and the number of committed progenitors, and cause alterations in T-cell development. Haploinsufficiency can contribute to inherited leukaemia syndromes, and some leukaemias seem to have amplification of the RUNX1 locus.
5. Chromosomal translocations target CBFs in human leukaemias. These include the RUNX1–ETO, CBFB–SMMHC and TEL–RUNX1 fusion genes. Biochemical and developmental studies indicate that these all encode dominant inhibitors of the native CBF complex (RUNX1–ETO, CBFβ–SMMHC and TEL–RUNX1), through recruitment of the nuclear corepressor complex.
6. These fusion genes contribute to the pathogenesis of leukaemia. Their expression seems to impair normal haematopoietic development, but is not sufficient to cause leukaemia. A two-hit model of disease pathogenesis for CBF leukaemias is presented.
7. CBF fusions, in general, confer a favourable prognosis in patients with leukaemia, although there is debate about the prognostic significance of the TEL–RUNX1 fusion in paediatric acute lymphoblastic leukaemia.
8. Therapeutic strategies for targeting CBF in leukaemia could include the use of histone-deacetylase inhibitors to disrupt the nuclear corepressor function that is mediated by the CBF fusions.

要点翻译：

1. 异二聚体转录因子核心结合因子（CBF）由RUNX1（亦称AML1、CBFA2和PEBP2αB）与CBFβ亚基构成。
2. RUNX1亚基直接接触DNA，而通过与不直接接触DNA的CBFβ亚基结合可显著提高其DNA结合亲和力。
3. CBF参与造血发育过程。基因敲除小鼠研究表明，CBF的两个亚基对于定型造血都是绝对必需的。
4. 在造血发育过程中，正确的CBF基因剂量至关重要。Runx1剂量的细微变化会显著影响干细胞出现的时间节点和定向祖细胞的数量，并导致T细胞发育异常。单倍体不足可能引发遗传性白血病综合征，而某些白血病似乎存在RUNX1基因座的扩增。
5. 染色体易位在人类白血病中靶向CBF，包括RUNX1-ETO、CBFB-SMMHC和TEL-RUNX1融合基因。生物化学与发育学研究显示，这些融合基因通过招募核共抑制因子复合体，编码天然CBF复合体（RUNX1-ETO、CBFβ-SMMHC和TEL-RUNX1）的显性抑制剂。
6. 这些融合基因参与白血病发病机制。其表达会损害正常造血发育，但尚不足以单独引发白血病。针对CBF白血病提出了"二次打击"发病模型。
7. 总体而言，CBF融合基因预示着白血病患者预后较好，但关于TEL-RUNX1融合在儿童急性淋巴细胞白血病中的预后意义仍存争议。
8. 针对白血病CBF靶点的治疗策略可能包括使用组蛋白去乙酰化酶抑制剂，以破坏CBF融合蛋白介导的核共抑制功能。

英文摘要：

Core-binding factors (CBFs) are a class of haematopoietic transcription factors that are crucial for the regulation of haematopoietic ontogeny, and are frequent targets of mutation and gene rearrangement in human leukaemia. So, what are the functions of CBFs during development, and what are the functional consequences of CBF mutations in leukaemia? Synergy between these convergent lines of enquiry has furthered our understanding of both normal and malignant haematopoiesis.

摘要翻译： 

核心结合因子（CBFs）是一类造血转录因子，对造血发育的调控至关重要，同时也是人类白血病中突变和基因重排的常见靶点。那么，CBFs在发育过程中发挥哪些功能？CBF突变在白血病中又会产生怎样的功能后果？这两条研究路径的协同作用，推动了我们对于正常与恶性造血机制的理解。

原文链接：

Core-binding factors in haematopoiesis and leukaemia