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

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. •Generation of an inducible and reversible mouse model for MLL-AF9-driven AML•The cell of origin controls aggressiveness and outcome of MLL-AF9-mediated AML•The EMT transcription factor ZEB1 controls AML cell migration and invasion•Expression of multiple EMT-related genes is associated with poor outcome in human AML Stavropoulou et al. show that MLL-AF9 expression in mouse long-term hematopoietic stem cells causes invasive, chemoresistant acute myeloid leukemia (AML) that expresses genes related to epithelial-mesenchymal transition (EMT). Expression of EMT-related genes in human AML is associated with poor patient survival.