Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
Northern Institute for Cancer Research, University of Newcastle, Newcastle, UK.
Nat Genet. 2019 Jan;51(1):151-162. doi: 10.1038/s41588-018-0270-1. Epub 2018 Nov 12.
Acute myeloid leukemia (AML) is a heterogeneous disease caused by a variety of alterations in transcription factors, epigenetic regulators and signaling molecules. To determine how different mutant regulators establish AML subtype-specific transcriptional networks, we performed a comprehensive global analysis of cis-regulatory element activity and interaction, transcription factor occupancy and gene expression patterns in purified leukemic blast cells. Here, we focused on specific subgroups of subjects carrying mutations in genes encoding transcription factors (RUNX1, CEBPα), signaling molecules (FTL3-ITD, RAS) and the nuclear protein NPM1). Integrated analysis of these data demonstrates that each mutant regulator establishes a specific transcriptional and signaling network unrelated to that seen in normal cells, sustaining the expression of unique sets of genes required for AML growth and maintenance.
急性髓系白血病（AML）是一种异质性疾病，由转录因子、表观遗传调节剂和信号分子的多种改变引起。为了确定不同的突变调节剂如何建立 AML 亚型特异性转录网络，我们在纯化的白血病母细胞中对顺式调节元件活性和相互作用、转录因子占据和基因表达模式进行了全面的全局分析。在这里，我们专注于携带编码转录因子（RUNX1、CEBPα）、信号分子（FTL3-ITD、RAS）和核蛋白 NPM1 的基因突变的特定亚组受试者。对这些数据的综合分析表明，每个突变调节剂都建立了一个特定的转录和信号网络，与正常细胞中看到的无关，维持 AML 生长和维持所需的独特基因集的表达。
