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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Vydáno v:	Cancer cell Ročník 30; číslo 1; s. 43 - 58
Hlavní autoři:	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
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States 11.07.2016
Témata:	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
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Popis
Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1878-3686
DOI:	10.1016/j.ccell.2016.05.011