Myeloid transformation by - depends strictly on C/EBP.

Chromosomal rearrangements of the mixed-lineage leukemia gene 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 - 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 / almost entirely abrogated the growth and survival of --transformed cells. Rare, slow-growing, and apoptosis-prone --transformed escapees were recovered from compound / deletions. The escapees were uniformly characterized by high expression of the resident 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. gene inactivation was accomplished only in the presence of complementing C/EBPβ, but not in its absence, confirming the dependency of the / double knockouts. Our data show that -transformed myeloid cells are dependent on C/EBPs during the initiation and maintenance of transformation.