Department of Biomedicine, University Children's Hospital (UKBB), University of Basel, 4031 Basel, Switzerland.
Friedrich Miescher Institute for Biomedical Research (FMI), Maulbeerstrasse 66, 4058 Basel, Switzerland; Faculty of Sciences, University of Basel, 4031 Basel, Switzerland.
Cancer Cell. 2016 Jul 11;30(1):43-58. doi: 10.1016/j.ccell.2016.05.011. Epub 2016 Jun 23.
To address the impact of cellular origin on acute myeloid leukemia (AML), we generated an inducible transgenic mouse model for MLL-AF9-driven leukemia. MLL-AF9 expression in long-term hematopoietic stem cells (LT-HSC) in vitro resulted in dispersed clonogenic growth and expression of genes involved in migration and invasion. In vivo, 20% LT-HSC-derived AML were particularly aggressive with extensive tissue infiltration, chemoresistance, and expressed genes related to epithelial-mesenchymal transition (EMT) in solid cancers. Knockdown of the EMT regulator ZEB1 significantly reduced leukemic blast invasion. By classifying mouse and human leukemias according to Evi1/EVI1 and Erg/ERG expression, reflecting aggressiveness and cell of origin, and performing comparative transcriptomics, we identified several EMT-related genes that were significantly associated with poor overall survival of AML patients.
为了研究细胞起源对急性髓细胞白血病（AML）的影响，我们构建了一个可诱导的 MLL-AF9 驱动的白血病转基因小鼠模型。在体外，MLL-AF9 在长期造血干细胞（LT-HSC）中的表达导致了分散的集落生成和参与迁移和侵袭的基因的表达。在体内，20%的 LT-HSC 衍生的 AML 特别具有侵袭性，广泛浸润组织，对化疗耐药，并表达与实体瘤中上皮-间充质转化（EMT）相关的基因。EMT 调节因子 ZEB1 的敲低显著降低了白血病母细胞的侵袭。通过根据 Evi1/EVI1 和 Erg/ERG 的表达对小鼠和人类白血病进行分类，反映侵袭性和细胞起源，并进行比较转录组学分析，我们鉴定了几个 EMT 相关基因，这些基因与 AML 患者的总体生存不良显著相关。
