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

  • Stavropoulou V Department of Biomedicine, University Children's Hospital (UKBB), University of Basel, 4031 Basel, Switzerland.
  • Kaspar S Friedrich Miescher Institute for Biomedical Research (FMI), Maulbeerstrasse 66, 4058 Basel, Switzerland; Faculty of Sciences, University of Basel, 4031 Basel, Switzerland.
  • Brault L Department of Biomedicine, University Children's Hospital (UKBB), University of Basel, 4031 Basel, Switzerland.
  • Sanders MA Department of Hematology, Erasmus University Medical Center, 3015 CE Rotterdam, the Netherlands.
  • Juge S Department of Biomedicine, University Children's Hospital (UKBB), University of Basel, 4031 Basel, Switzerland.
  • Morettini S Friedrich Miescher Institute for Biomedical Research (FMI), Maulbeerstrasse 66, 4058 Basel, Switzerland.
  • Tzankov A Institute for Pathology, University Hospital Basel, 4031 Basel, Switzerland.
  • Iacovino M Department of Pediatrics, LA Biomedical Research Institute, Torrance, CA 90502, USA.
  • Lau IJ MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, NIHR Oxford Biomedical Research Centre Programme, University of Oxford, Oxford OX3 9DS, UK.
  • Milne TA MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, NIHR Oxford Biomedical Research Centre Programme, University of Oxford, Oxford OX3 9DS, UK.
  • Royo H Friedrich Miescher Institute for Biomedical Research (FMI), Maulbeerstrasse 66, 4058 Basel, Switzerland.
  • Kyba M Department of Pediatrics, Lillehei Heart Institute, University of Minnesota, Minneapolis, MN 55455, USA.
  • Valk PJM Department of Hematology, Erasmus University Medical Center, 3015 CE Rotterdam, the Netherlands.
  • Peters AHFM 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.
  • Schwaller J Department of Biomedicine, University Children's Hospital (UKBB), University of Basel, 4031 Basel, Switzerland. Electronic address: j.schwaller@unibas.ch.
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  • 2016-06-28
Published in:
  • Cancer cell. - 2016
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
English 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.
Language
  • English
Open access status
bronze
Identifiers
Persistent URL
https://sonar.ch/global/documents/232181
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