The Finsen Laboratory, Rigshospitalet, Faculty of Health Sciences; 2 Biotech Research and Innovation Center (BRIC); 3 Danish Stem Cell Centre (DanStem) Faculty of Health Sciences; 4 The Bioinformatic Centre, Department of Biology, Faculty of Natural Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
J Exp Med. 2014 Jan 13;211(1):5-13. doi: 10.1084/jem.20130932. Epub 2013 Dec 23.
MLL-fusion proteins are potent inducers of oncogenic transformation, and their expression is considered to be the main oncogenic driving force in ∼10% of human acute myeloid leukemia (AML) patients. These oncogenic fusion proteins are responsible for the initiation of a downstream transcriptional program leading to the expression of factors such as MEIS1 and HOXA9, which in turn can replace MLL-fusion proteins in overexpression experiments. To what extent MLL fusion proteins act on their own during tumor initiation, or if they collaborate with other transcriptional regulators, is unclear. Here, we have compared gene expression profiles from human MLL-rearranged AML to normal progenitors and identified the myeloid tumor suppressor C/EBPα as a putative collaborator in MLL-rearranged AML. Interestingly, we find that deletion of Cebpa rendered murine hematopoietic progenitors completely resistant to MLL-ENL-induced leukemic transformation, whereas C/EBPα was dispensable in already established AMLs. Furthermore, we show that Cebpa-deficient granulocytic-monocytic progenitors were equally resistant to transformation and that C/EBPα collaborates with MLL-ENL in the induction of a transcriptional program, which is also apparent in human AML. Thus, our studies demonstrate a key role of C/EBPα in MLL fusion-driven transformation and find that it sharply demarcates tumor initiation and maintenance.
MLL 融合蛋白是致癌转化的有力诱导剂，其表达被认为是约 10%人类急性髓系白血病（AML）患者的主要致癌驱动力。这些致癌融合蛋白负责启动下游转录程序，导致 MEIS1 和 HOXA9 等因子的表达，而这些因子反过来可以在过表达实验中替代 MLL 融合蛋白。MLL 融合蛋白在肿瘤起始过程中是单独起作用，还是与其他转录调节剂协同作用，目前尚不清楚。在这里，我们比较了人类 MLL 重排 AML 与正常祖细胞的基因表达谱，并鉴定出髓系肿瘤抑制因子 C/EBPα 是 MLL 重排 AML 中的一个潜在协同因子。有趣的是，我们发现 Cebpa 的缺失使小鼠造血祖细胞完全抵抗 MLL-ENL 诱导的白血病转化，而 C/EBPα 在已经建立的 AML 中是可有可无的。此外，我们表明，Cebpa 缺陷的粒细胞-单核细胞祖细胞同样抵抗转化，并且 C/EBPα 与 MLL-ENL 合作诱导转录程序，这在人类 AML 中也很明显。因此，我们的研究表明 C/EBPα 在 MLL 融合驱动的转化中起着关键作用，并发现它明确地划分了肿瘤起始和维持。
