Acute myeloid leukemia (AML) is characterized by impaired myeloid lineage differentiation, uncontrolled proliferation and inhibition of pro-apoptotic pathways. In spite of a relatively homogenous clinical disease presentation, risk of long-term survival in AML varies from 20-80% depending on molecular disease characteristics. In recognition of the molecular heterogeneity of AML, the European Leukemia Net (ELN) and WHO classification systems now incorporate cytogenetics and increasing numbers of gene mutations into AML prognostication. Several of the genomic AML subsets are characterized by unique transcription factor alterations which are highlighted in this review. There are many mechanisms of transcriptional deregulation in leukemia. We broadly classify transcription factors based on mechanisms of transcriptional deregulation including direct involvement of transcription factors in recurrent translocations, loss of function mutations, and intracellular relocalization. Transcription factors, due to their pleiotropic effects have been attractive but elusive targets. Indirect targeting approaches include inhibition of upstream kinases such as TAK1 for suppression of NFκB signaling and downstream effectors such as FGF signaling in HOXA-upregulated leukemia. Other strategies include targeting scaffolding proteins like BrD4 in the case of MYC or coactivators such as menin to suppress HOX expression; disrupting critical protein interactions in the case of β-catenin: TCF/LEF , and preventing transcription factor binding to DNA as in the case of PU.1 or FOXM1. We comprehensively describe the mechanism of deregulation of transcription factors in genomic subsets of AML, consequent pathway addictions and potential therapeutic strategies.

中文翻译：

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AML中转录因子的治疗脆弱性

急性髓性白血病 (AML) 的特征是髓系分化受损、增殖失控和促凋亡途径受到抑制。尽管具有相对同质的临床疾病表现，但 AML 的长期生存风险在 20-80% 之间变化，具体取决于分子疾病特征。鉴于 AML 的分子异质性，欧洲白血病网 (ELN) 和 WHO 分类系统现在将细胞遗传学和越来越多的基因突变纳入 AML 预后。几个基因组 AML 子集的特点是独特的转录因子改变，本综述强调了这些改变。白血病中存在许多转录失调机制。我们根据转录失调的机制对转录因子进行广泛分类，包括转录因子直接参与反复易位、功能突变丧失和细胞内重新定位。转录因子因其多效性而成为有吸引力但难以捉摸的目标。间接靶向方法包括抑制上游激酶（如 TAK1）以抑制 NFκB 信号传导和下游效应器（如 HOXA 上调白血病中的 FGF 信号传导）。其他策略包括在 MYC 的情况下靶向支架蛋白（如 BrD4）或共激活因子（如 menin）以抑制 HOX 表达；在 β-连环蛋白的情况下破坏关键的蛋白质相互作用：TCF/LEF，并阻止转录因子与 DNA 结合，如 PU.1 或 FOXM1 的情况。