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.

中文翻译：

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MLL-ENL 的髓系转化严格依赖于 C/EBP。

混合谱系白血病基因MLL1 的染色体重排是婴儿急性白血病的标志。粒细胞-巨噬细胞祖细胞状态形成了骨髓单核细胞白血病干细胞和 MLL 型癌蛋白转化的表观遗传基础。以前，表明小鼠骨髓单核细胞MLL - ENL转化的建立，而不是其维持，取决于转录因子 C/EBPα，表明 MLL 驱动的肿瘤发生的表观遗传命中和运行机制。在这里，我们证明了Cebpa / Cebpb 的复合缺失几乎完全废除了MLL - ENL的生长和存活- 转化细胞。从复合Cebpa / Cebpb缺失中回收了罕见的、生长缓慢且易于凋亡的MLL - ENL转化的逃逸者。逃逸者的特征是常驻Cebpe基因的高表达，表明 C/EBPε 对 C/EBPα/C/EBPβ 缺乏的功能补偿较差。异位 C/EBPβ 表达和 IGF1 下游激活增强了互补性，从而增强了生长。Cebpe基因失活仅在存在补充 C/EBPβ 的情况下完成，但在不存在的情况下无法实现，证实了Cebpa / Cebpb的Cebpe依赖性双淘汰赛。我们的数据显示MLL转化的骨髓细胞在转化的起始和维持期间依赖于 C/EBP。