Kellaway Sophie, Chin Paulynn S, Barneh Farnaz, Bonifer Constanze, Heidenreich Olaf
Institute of Cancer and Genomica Sciences, College of Medicine and Dentistry, University of Birmingham, Birmingham B152TT, UK.
Princess Máxima Centrum for Pediatric Oncology, Heidelberglaan 25, 3584CS Utrecht, The Netherlands.
Cells. 2020 Dec 13;9(12):2681. doi: 10.3390/cells9122681.
Acute myeloid leukemia (AML) is a heterogenous disease with multiple sub-types which are defined by different somatic mutations that cause blood cell differentiation to go astray. Mutations occur in genes encoding members of the cellular machinery controlling transcription and chromatin structure, including transcription factors, chromatin modifiers, DNA-methyltransferases, but also signaling molecules that activate inducible transcription factors controlling gene expression and cell growth. Mutant cells in AML patients are unable to differentiate and adopt new identities that are shaped by the original driver mutation and by rewiring their gene regulatory networks into regulatory phenotypes with enhanced fitness. One of the best-studied AML-subtypes is the t(8;21) AML which carries a translocation fusing the DNA-binding domain of the hematopoietic master regulator RUNX1 to the ETO gene. The resulting oncoprotein, RUNX1/ETO has been studied for decades, both at the biochemical but also at the systems biology level. It functions as a dominant-negative version of RUNX1 and interferes with multiple cellular processes associated with myeloid differentiation, growth regulation and genome stability. In this review, we summarize our current knowledge of how this protein reprograms normal into malignant cells and how our current knowledge could be harnessed to treat the disease.
急性髓系白血病（AML）是一种异质性疾病，有多种亚型，这些亚型由不同的体细胞突变所定义，这些突变导致血细胞分化误入歧途。突变发生在编码控制转录和染色质结构的细胞机制成员的基因中，包括转录因子、染色质修饰因子、DNA甲基转移酶，还有激活控制基因表达和细胞生长的诱导型转录因子的信号分子。AML患者中的突变细胞无法分化并获得新的特性，这些特性由最初的驱动突变以及通过将其基因调控网络重编程为具有更高适应性的调控表型所塑造。研究得最透彻的AML亚型之一是t(8;21) AML，它携带一种易位，将造血主调节因子RUNX1的DNA结合结构域与ETO基因融合。由此产生的致癌蛋白RUNX1/ETO已经被研究了几十年，无论是在生化水平还是系统生物学水平。它作为RUNX1的显性负性形式发挥作用，并干扰与髓系分化、生长调节和基因组稳定性相关的多个细胞过程。在这篇综述中，我们总结了我们目前关于这种蛋白质如何将正常细胞重编程为恶性细胞的知识，以及如何利用我们目前的知识来治疗这种疾病。
