Department of Genetics, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.
Leukemia. 2023 Sep;37(9):1850-1859. doi: 10.1038/s41375-023-01989-8. Epub 2023 Aug 2.
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.
转录因子 CCAAT 增强子结合因子α（C/ebpα）是髓样分化的主要控制器，以长（p42）和短（p30）异构体形式表达。CEBPA 基因内选择性缺失 p42 的突变在人类急性髓系白血病中很常见。在这里，我们研究了 p42 和 p30 的个体基因组学和转录组学。这两种蛋白质在整个基因组中结合到相同的位点。对于大多数靶点，它们诱导出高度相似的转录反应，但也有少数异构体特异性基因除外。在这些基因中，我们鉴定出早期生长反应 1（Egr1）和 Tribbles1（Trib1）是 p42 选择性诱导的关键靶点，这些靶点在 CEBPA 突变的 AML 中也表达不足。Egr1 执行髓样分化和生长抑制程序。相反，Trib1 通过激活 Erk1/2 激酶建立了负反馈回路，从而使分化受到信号的控制。出乎意料的是，无论是通过去除致癌输入还是通过 G-CSF 诱导的分化，都没有将 C/ebpα作为介质，而是通过上调 p21/p27 抑制剂直接影响细胞周期核心。这表明 C/ebpα 下游的功能是转化和分化刺激汇聚的交汇点，这一发现为治疗干预提供了一个新的视角。
