Singh Abhishek A, Mandoli Amit, Prange Koen H M, Laakso Marko, Martens Joost H A
Radboud University, Department of Molecular Biology, Faculty of Science, Nijmegen Centre for Molecular Life Sciences, 6500 HB Nijmegen, The Netherlands.
Genome Scale Biology Research Program, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
Oncotarget. 2017 Feb 21;8(8):12855-12865. doi: 10.18632/oncotarget.14150.
Chromosomal translocations are one of the hallmarks of acute myeloid leukemia (AML), often leading to gene fusions and expression of an oncofusion protein. Over recent years it has become clear that most of the AML associated oncofusion proteins molecularly adopt distinct mechanisms for inducing leukemogenesis. Still these unique molecular properties of the chimeric proteins converge and give rise to a common pathogenic molecular mechanism. In the present study we compared genome-wide DNA binding and transcriptome data associated with AML1-ETO, CBFB-MYH11 and PML-RARA oncofusion protein expression to identify unique and common features. Our analyses revealed targeting of oncofusion binding sites to RUNX1 and ETS-factor occupied genomic regions. In addition, it revealed a highly comparable global histone acetylation pattern, similar expression of common target genes and related enrichment of several biological pathways critical for maintenance of AML, suggesting oncofusion proteins deregulate common gene programs despite their distinct binding signatures and mechanisms of action.
染色体易位是急性髓系白血病（AML）的特征之一，常导致基因融合和癌融合蛋白的表达。近年来，越来越清楚的是，大多数与AML相关的癌融合蛋白在分子水平上采用不同的机制诱导白血病发生。尽管如此，这些嵌合蛋白独特的分子特性汇聚在一起，产生了一种共同的致病分子机制。在本研究中，我们比较了与AML1-ETO、CBFB-MYH11和PML-RARA癌融合蛋白表达相关的全基因组DNA结合和转录组数据，以识别独特和共同的特征。我们的分析揭示了癌融合结合位点靶向RUNX1和ETS因子占据的基因组区域。此外，还揭示了高度可比的整体组蛋白乙酰化模式、共同靶基因的相似表达以及对维持AML至关重要的几种生物学途径的相关富集，这表明癌融合蛋白尽管具有不同的结合特征和作用机制，但仍会使共同的基因程序失调。
