MLL-AF9 在造血干细胞中的表达驱动高侵袭性 AML 表达 EMT 相关基因，与不良预后相关。

MLL-AF9 Expression in Hematopoietic Stem Cells Drives a Highly Invasive AML Expressing EMT-Related Genes Linked to Poor Outcome.

机构信息

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.

出版信息

Cancer Cell. 2016 Jul 11;30(1):43-58. doi: 10.1016/j.ccell.2016.05.011. Epub 2016 Jun 23.

DOI:10.1016/j.ccell.2016.05.011

PMID:27344946

Abstract

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.

摘要

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。