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 的骨髓转化严格取决于 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粒单核细胞白血病干性和 MLL 型癌蛋白转化的表观遗传基础。此前，研究表明，小鼠骨髓单核细胞MLL - ENL转化的建立，而不是其维持，依赖于转录因子C/EBPα，这表明MLL驱动的肿瘤发生存在表观遗传的“打了就跑”机制。在这里，我们证明Cebpa / Cebpb的复合缺失几乎完全消除了MLL - ENL转化细胞的生长和存活。从复合Cebpa / Cebpb缺失中回收了罕见、生长缓慢且易于凋亡的MLL - ENL转化逃逸细胞。逃亡者的一致特征是常驻Cebpe基因的高表达，这表明 C/EBPε 对 C/EBPα/C/EBPβ 缺陷的功能补偿较差。异位 C/EBPβ 表达和下游 IGF1 激活增强了互补作用，从而增强了生长。 Cebpe基因失活仅在互补 C/EBPβ 存在的情况下完成，但在其不存在的情况下则不然，证实了Cebpa / Cebpb双敲除的Cebpe依赖性。我们的数据表明， MLL转化的骨髓细胞在转化的起始和维持过程中依赖于 C/EBP。