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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.

Original publication

DOI

10.1016/j.ccell.2016.05.011

Type

Journal article

Journal

Cancer Cell

Publication Date

07/2016

Volume

30

Pages

43 - 58

Keywords

EMT, MLL-AF9, acute myeloid leukemia, invasion, poor overall survival, stem cell, Animals, Drug Resistance, Neoplasm, Epithelial-Mesenchymal Transition, Gene Expression Profiling, Gene Expression Regulation, Leukemic, Hematopoietic Stem Cell Transplantation, Hematopoietic Stem Cells, Humans, Leukemia, Myeloid, Acute, Mice, Mice, Transgenic, Myeloid-Lymphoid Leukemia Protein, Neoplasm Invasiveness, Neoplasms, Experimental, Oncogene Proteins, Fusion, Prognosis, Tumor Cells, Cultured, Zinc Finger E-box-Binding Homeobox 1