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

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...

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Bibliographic Details
Published in:Cancer cell Vol. 30; no. 1; pp. 43 - 58
Main Authors: Stavropoulou, Vaia, Kaspar, Susanne, Brault, Laurent, Sanders, Mathijs A, Juge, Sabine, Morettini, Stefano, Tzankov, Alexandar, Iacovino, Michelina, Lau, I-Jun, Milne, Thomas A, Royo, Hélène, Kyba, Michael, Valk, Peter J M, Peters, Antoine H F M, Schwaller, Juerg
Format: Journal Article
Language:English
Published: United States 11.07.2016
Subjects:
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
MLL-AF9
acute myeloid leukemia
invasion
stem cell
poor overall survival
EMT
ISSN:1878-3686
Online Access:Get more information
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Summary: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.
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ISSN:1878-3686
DOI:10.1016/j.ccell.2016.05.011