title: MLL-AF9 Expression in Hematopoietic Stem Cells Drives a Highly Invasive AML Expressing EMT-Related Genes Linked to Poor Outcome.
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.
authors.affiliation: Department of Biomedicine, University Children's Hospital (UKBB), University of Basel, 4031 Basel, Switzerland.
authors.forename: Vaia
authors.initials: V
authors.lastname: Stavropoulou
authors.affiliation: Friedrich Miescher Institute for Biomedical Research (FMI), Maulbeerstrasse 66, 4058 Basel, Switzerland; Faculty of Sciences, University of Basel, 4031 Basel, Switzerland.
authors.forename: Susanne
authors.initials: S
authors.lastname: Kaspar
authors.affiliation: Department of Biomedicine, University Children's Hospital (UKBB), University of Basel, 4031 Basel, Switzerland.
authors.forename: Laurent
authors.initials: L
authors.lastname: Brault
authors.affiliation: Department of Hematology, Erasmus University Medical Center, 3015 CE Rotterdam, the Netherlands.
authors.forename: Mathijs A
authors.initials: MA
authors.lastname: Sanders
authors.affiliation: Department of Biomedicine, University Children's Hospital (UKBB), University of Basel, 4031 Basel, Switzerland.
authors.forename: Sabine
authors.initials: S
authors.lastname: Juge
authors.affiliation: Friedrich Miescher Institute for Biomedical Research (FMI), Maulbeerstrasse 66, 4058 Basel, Switzerland.
authors.forename: Stefano
authors.initials: S
authors.lastname: Morettini
authors.affiliation: Institute for Pathology, University Hospital Basel, 4031 Basel, Switzerland.
authors.forename: Alexandar
authors.initials: A
authors.lastname: Tzankov
authors.affiliation: Department of Pediatrics, LA Biomedical Research Institute, Torrance, CA 90502, USA.
authors.forename: Michelina
authors.initials: M
authors.lastname: Iacovino
authors.affiliation: MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, NIHR Oxford Biomedical Research Centre Programme, University of Oxford, Oxford OX3 9DS, UK.
authors.forename: I-Jun
authors.initials: IJ
authors.lastname: Lau
authors.affiliation: MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, NIHR Oxford Biomedical Research Centre Programme, University of Oxford, Oxford OX3 9DS, UK.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Milne
authors.affiliation: Friedrich Miescher Institute for Biomedical Research (FMI), Maulbeerstrasse 66, 4058 Basel, Switzerland.
authors.forename: Hélène
authors.initials: H
authors.lastname: Royo
authors.affiliation: Department of Pediatrics, Lillehei Heart Institute, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Kyba
authors.affiliation: Department of Hematology, Erasmus University Medical Center, 3015 CE Rotterdam, the Netherlands.
authors.forename: Peter J M
authors.initials: PJM
authors.lastname: Valk
authors.affiliation: Friedrich Miescher Institute for Biomedical Research (FMI), Maulbeerstrasse 66, 4058 Basel, Switzerland; Faculty of Sciences, University of Basel, 4031 Basel, Switzerland. Electronic address: antoine.peters@fmi.ch.
authors.forename: Antoine H F M
authors.initials: AHFM
authors.lastname: Peters
authors.affiliation: Department of Biomedicine, University Children's Hospital (UKBB), University of Basel, 4031 Basel, Switzerland. Electronic address: j.schwaller@unibas.ch.
authors.forename: Juerg
authors.initials: J
authors.lastname: Schwaller
mesh_terms: D000818:Animals; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition; D020869:Gene Expression Profiling / Q000379:methods; D015973:Gene Expression Regulation, Leukemic; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics* / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009374:Neoplasms, Experimental; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism*; D011379:Prognosis; D014407:Tumor Cells, Cultured; D000071799:Zinc Finger E-box-Binding Homeobox 1 / Q000235:genetics
chemical_list: C474558:MLL-AF9 fusion protein, human; D015514:Oncogene Proteins, Fusion; C486307:ZEB1 protein, human; C519422:ZEB1 protein, mouse; D000071799:Zinc Finger E-box-Binding Homeobox 1; D051788:Myeloid-Lymphoid Leukemia Protein
keywords: EMT; MLL-AF9; acute myeloid leukemia; invasion; poor overall survival; stem cell