转录因子CCAAT启动子结合因子α（C/ebpα）是一种控制髓系分化的主要调控因子，由长（p42）和短（p30）两种异构体表达。CEBPA基因内的突变会选择性地删除p42，在人类急性髓系白血病中频繁出现。本研究调查了p42和p30的个体基因组和转录组。这两种蛋白在基因组中结合到相同的位点。对于大多数靶点，它们引起了高度相似的转录反应，但也有一些异构体特异基因的例外。在这些基因中，我们确定早期增长应答1（Egr1）和三胞霉素1（Trib1）作为p42选择性诱导的关键靶点，它们在CEBPA突变AML中也呈低表达。Egr1执行了髓系分化和生长抑制程序。相反，Trib1通过激活Erk1/2激酶建立了一个负反馈环路，从而将分化置于信号控制之下。出乎意料的是，通过消除致癌因子的作用或通过G-CSF诱导的分化并不依赖C/ebpα作为介导因子，而是通过上调p21/p27抑制剂来直接影响细胞周期核心。这表明C/ebpα下游功能是转化和分化刺激汇集的交汇点，这一发现为治疗干预提供了新的视角。© 2023. 作者。

The transcription factor CCAAT-enhancer binding factor alpha (C/ebpα) is a master controller of myeloid differentiation that is expressed as long (p42) and short (p30) isoform. Mutations within the CEBPA gene selectively deleting p42 are frequent in human acute myeloid leukemia. Here we investigated the individual genomics and transcriptomics of p42 and p30. Both proteins bound to identical sites across the genome. For most targets, they induced a highly similar transcriptional response with the exception of a few isoform specific genes. Amongst those we identified early growth response 1 (Egr1) and tribbles1 (Trib1) as key targets selectively induced by p42 that are also underrepresented in CEBPA-mutated AML. Egr1 executed a program of myeloid differentiation and growth arrest. Oppositely, Trib1 established a negative feedback loop through activation of Erk1/2 kinase thus placing differentiation under control of signaling. Unexpectedly, differentiation elicited either by removal of an oncogenic input or by G-CSF did not peruse C/ebpα as mediator but rather directly affected the cell cycle core by upregulation of p21/p27 inhibitors. This points to functions downstream of C/ebpα as intersection point where transforming and differentiation stimuli converge and this finding offers a new perspective for therapeutic intervention.© 2023. The Author(s).