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Myeloid transformation by MLL-ENL depends strictly on C/EBP

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Item Type:Article
Title:Myeloid transformation by MLL-ENL depends strictly on C/EBP
Creators Name:Wesolowski, R. and Kowenz-Leutz, E. and Zimmermann, K. and Dörr, D. and Hofstätter, M. and Slany, R.K. and Mildner, A. and Leutz, A.
Abstract:Chromosomal rearrangements of the mixed-lineage leukemia gene MLL1 are the hallmark of infant acute leukemia. The granulocyte-macrophage progenitor state forms the epigenetic basis for myelomonocytic leukemia stemness and transformation by MLL-type oncoproteins. Previously, it was shown that the establishment of murine myelomonocytic MLL-ENL transformation, but not its maintenance, depends on the transcription factor C/EBPα, suggesting an epigenetic hit-and-run mechanism of MLL-driven oncogenesis. Here, we demonstrate that compound deletion of Cebpa/Cebpb almost entirely abrogated the growth and survival of MLL-ENL–transformed cells. Rare, slow-growing, and apoptosis-prone MLL-ENL–transformed escapees were recovered from compound Cebpa/Cebpb deletions. The escapees were uniformly characterized by high expression of the resident Cebpe gene, suggesting inferior functional compensation of C/EBPα/C/EBPβ deficiency by C/EBPε. Complementation was augmented by ectopic C/EBPβ expression and downstream activation of IGF1 that enhanced growth. Cebpe gene inactivation was accomplished only in the presence of complementing C/EBPβ, but not in its absence, confirming the Cebpe dependency of the Cebpa/Cebpb double knockouts. Our data show that MLL-transformed myeloid cells are dependent on C/EBPs during the initiation and maintenance of transformation.
Keywords:Acute Leukemia, Myeloid, Apoptosis, CCAAT-Enhancer-Binding Protein-alpha, CCAAT-Enhancer-Binding Protein-beta, CCAAT-Enhancer-Binding Proteins, Cell Proliferation, Cell Survival, Fusion Oncogene Proteins, Gene Knockout Techniques, Granulocyte Precursor Cells, HEK293 Cells, Myeloid-Lymphoid Leukemia Protein, Neoplastic Cell Transformation, Signal Transduction, Transfection, Animals, Mice
Source:Life Science Alliance
Publisher:Life Science Alliance
Page Range:e202000709
Date:January 2021
Official Publication:https://doi.org/10.26508/lsa.202000709
PubMed:View item in PubMed

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