@article {Wesolowskie202000709, author = {Radoslaw Wesolowski and Elisabeth Kowenz-Leutz and Karin Zimmermann and Dorothea D{\"o}rr and Maria Hofst{\"a}tter and Robert K Slany and Alexander Mildner and Achim Leutz}, title = {Myeloid transformation by MLL-ENL depends strictly on C/EBP}, volume = {4}, number = {1}, elocation-id = {e202000709}, year = {2021}, doi = {10.26508/lsa.202000709}, publisher = {Life Science Alliance}, 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{\textendash}transformed cells. Rare, slow-growing, and apoptosis-prone MLL-ENL{\textendash}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.}, URL = {https://www.life-science-alliance.org/content/4/1/e202000709}, eprint = {https://www.life-science-alliance.org/content/4/1/e202000709.full.pdf}, journal = {Life Science Alliance} }