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

Radoslaw Wesolowski, Elisabeth Kowenz-Leutz, Karin Zimmermann, Dorothea Dörr, Maria Hofstätter, Robert K Slany, Alexander Mildner, Achim Leutz

Life science alliance 2021 Jan

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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. © 2020 Wesolowski et al.

Citation

Radoslaw Wesolowski, Elisabeth Kowenz-Leutz, Karin Zimmermann, Dorothea Dörr, Maria Hofstätter, Robert K Slany, Alexander Mildner, Achim Leutz. Myeloid transformation by MLL-ENL depends strictly on C/EBP. Life science alliance. 2021 Jan;4(1)