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

doi:10.1016/j.ccell.2016.05.011

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

Cancer Cell. 2016 Jul 11;30(1):43-58. doi: 10.1016/j.ccell.2016.05.011. Epub 2016 Jun 23.

Authors

Affiliations

¹ Department of Biomedicine, University Children's Hospital (UKBB), University of Basel, 4031 Basel, Switzerland.
² Friedrich Miescher Institute for Biomedical Research (FMI), Maulbeerstrasse 66, 4058 Basel, Switzerland; Faculty of Sciences, University of Basel, 4031 Basel, Switzerland.
³ Department of Hematology, Erasmus University Medical Center, 3015 CE Rotterdam, the Netherlands.
⁴ Friedrich Miescher Institute for Biomedical Research (FMI), Maulbeerstrasse 66, 4058 Basel, Switzerland.
⁵ Institute for Pathology, University Hospital Basel, 4031 Basel, Switzerland.
⁶ Department of Pediatrics, LA Biomedical Research Institute, Torrance, CA 90502, USA.
⁷ MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, NIHR Oxford Biomedical Research Centre Programme, University of Oxford, Oxford OX3 9DS, UK.
⁸ Department of Pediatrics, Lillehei Heart Institute, University of Minnesota, Minneapolis, MN 55455, USA.
⁹ 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.
¹⁰ Department of Biomedicine, University Children's Hospital (UKBB), University of Basel, 4031 Basel, Switzerland. Electronic address: j.schwaller@unibas.ch.

PMID: 27344946
DOI: 10.1016/j.ccell.2016.05.011

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.

Keywords: EMT; MLL-AF9; acute myeloid leukemia; invasion; poor overall survival; stem cell.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Drug Resistance, Neoplasm
Epithelial-Mesenchymal Transition*
Gene Expression Profiling / methods
Gene Expression Regulation, Leukemic
Hematopoietic Stem Cell Transplantation
Hematopoietic Stem Cells / cytology*
Hematopoietic Stem Cells / metabolism
Humans
Leukemia, Myeloid, Acute / genetics*
Leukemia, Myeloid, Acute / metabolism
Leukemia, Myeloid, Acute / pathology*
Mice
Mice, Transgenic
Myeloid-Lymphoid Leukemia Protein / genetics*
Myeloid-Lymphoid Leukemia Protein / metabolism*
Neoplasm Invasiveness
Neoplasms, Experimental
Oncogene Proteins, Fusion / genetics*
Oncogene Proteins, Fusion / metabolism*
Prognosis
Tumor Cells, Cultured
Zinc Finger E-box-Binding Homeobox 1 / genetics

Substances

MLL-AF9 fusion protein, human
Oncogene Proteins, Fusion
ZEB1 protein, human
ZEB1 protein, mouse
Zinc Finger E-box-Binding Homeobox 1
Myeloid-Lymphoid Leukemia Protein