Changes in the transcriptional machinery cause aberrant self-renewal of non-stem hematopoietic progenitors. AF10 fusions, such as CALM-AF10, are generated via chromosomal translocations, causing malignant leukemia. In this study, we demonstrate that AF10 fusion proteins cause aberrant self-renewal via ENL, which binds to MOZ/MORF lysine acetyltransferases (KATs). The interaction of ENL with MOZ, via its YEATS domain, is critical for CALM-AF10-mediated leukemic transformation. The MOZ/ENL complex recruits DOT1L/AF10 fusion complexes and maintains their chromatin retention via KAT activity. Therefore, inhibitors of MOZ/MORF KATs directly suppress the functions of AF10 fusion proteins, thereby exhibiting strong antitumor effects on AF10 translocation-induced leukemia. Combinatorial inhibition of MOZ/MORF and DOT1L cooperatively induces differentiation of CALM-AF10-leukemia cells. These results reveal roles for the MOZ/ENL complex as an essential recruiting factor of the AF10 fusion/DOT1L complex, providing a rationale for using MOZ/MORF KAT inhibitors in AF10 translocation-induced leukemia.

转录机制的变化导致非干细胞造血祖细胞的异常自我更新。AF10 融合，如 CALM-AF10，通过染色体易位产生，导致恶性白血病。在这项研究中，我们证明 AF10 融合蛋白通过 ENL 引起异常的自我更新，ENL 与 MOZ/MORF 赖氨酸乙酰转移酶 (KAT) 结合。ENL 与 MOZ 通过其 YEATS 结构域相互作用，对于 CALM-AF10 介导的白血病转化至关重要。MOZ/ENL 复合物募集 DOT1L/AF10 融合复合物并通过 KAT 活性维持其染色质保留。因此，MOZ/MORF KATs抑制剂直接抑制AF10融合蛋白的功能，从而对AF10表现出很强的抗肿瘤作用易位引起的白血病。MOZ/MORF 和 DOT1L 的组合抑制协同诱导 CALM-AF10-白血病细胞的分化。这些结果揭示了 MOZ/ENL 复合物作为 AF10 融合/DOT1L 复合物的重要募集因子的作用，为在AF10易位诱导的白血病中使用 MOZ/MORF KAT 抑制剂提供了基本原理。