TY - JOUR T1 - Myeloid transformation by <em>MLL</em>-<em>ENL</em> depends strictly on C/EBP JF - Life Science Alliance JO - Life Sci. Alliance DO - 10.26508/lsa.202000709 VL - 4 IS - 1 SP - e202000709 AU - Radoslaw Wesolowski AU - Elisabeth Kowenz-Leutz AU - Karin Zimmermann AU - Dorothea Dörr AU - Maria Hofstätter AU - Robert K Slany AU - Alexander Mildner AU - Achim Leutz Y1 - 2021/01/01 UR - https://www.life-science-alliance.org/content/4/1/e202000709.abstract N2 - 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. ER -