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

Vaia Stavropoulou, Susanne Kaspar, Laurent Brault, Mathijs A. Sanders, Sabine Juge, Stefano Morettini, Alexandar Tzankov, Michelina Iacovino, I. Jun Lau, Thomas A. Milne, Hélène Royo, Michael Kyba, Peter J M Valk, Antoine H F M Peters, Juerg Schwaller

Research output: Contribution to journalArticlepeer-review

79 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)43-58
Number of pages16
JournalCancer Cell
Volume30
Issue number1
DOIs
StatePublished - Jul 11 2016

Bibliographical note

Funding 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.

Keywords

  • EMT
  • MLL-AF9
  • acute myeloid leukemia
  • invasion
  • poor overall survival
  • stem cell

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