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.
Bibliographical noteFunding Information:
We thank Dr. J.L. Hess (Ann Arbor, USA) for the pMSCV-MLL-AF9 plasmid, and E. Traunecker, T. Krebs, U. Schneider and his team for FACS and animal husbandry support. We acknowledge the FMI members: M.B. Stadler for computational support, T. Roloff and his team for transcriptional profiling, J.F. Spetz, P. Kopp, and B. Kuchemann for generating iMLL-AF9 mice, and J. Tjeertes for discussions. A.H.F.M.P.’s laboratory was supported by: Novartis Research Foundation , SystemsX.ch (Cell plasticity), and EMBO YIP program . J.S.’s laboratory was supported by: Swiss National Science Foundation ( SNF-31003A_130661 & 31003A_149714/1 ), Swiss Cancer League ( OCS-2357-02-2009 , OCS-02778-02-2011 , KFS-3019-08-2012 ), Wilhelm Sander Foundation (Munich), Novartis Research Foundation , Swiss Bridge Foundation , and the Gertrude Von Meissner Foundation Basel. H.R. thanks the FP7-PEOPLE-2013-IEF grant. T.A.M. was supported by a Medical Research Council (UK) Molecular Hematology Unit grant MC_UU_12009/6 and I.-J.L. by an MRC UK Clinical Research Training Fellowship MR/M003221/1 . T.A.M. is a founding shareholder of Oxstem Oncology, a subsidiary company of OxStem Ltd.
- acute myeloid leukemia
- poor overall survival
- stem cell