MOZ/ENL 复合物是白血病 AF10 融合蛋白的募集因子。
MOZ/ENL complex is a recruiting factor of leukemic AF10 fusion proteins.
机构信息
Tsuruoka Metabolomics Laboratory, National Cancer Center, Tsuruoka, Yamagata, 997-0052, Japan.
Laboratory of Systems Genomics, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, the University of Tokyo, Kashiwa, Chiba, 277-0882, Japan.
出版信息
Nat Commun. 2023 Apr 8;14(1):1979. doi: 10.1038/s41467-023-37712-5.
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.
转录机制的改变导致非造血干祖细胞的异常自我更新。AF10 融合蛋白，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 融合蛋白通过与 MOZ/MORF 赖氨酸乙酰转移酶（KAT）结合的 ENL 导致异常自我更新。ENL 通过其 YEATS 结构域与 MOZ 的相互作用对于 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 KAT 抑制剂直接抑制 AF10 融合蛋白的功能，从而对 AF10 易位诱导的白血病表现出强烈的抗肿瘤作用。MOZ/MORF 和 DOT1L 的联合抑制协同诱导 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 复合物的必需募集因子的作用，为在 AF10 易位诱导的白血病中使用 MOZ/MORF KAT 抑制剂提供了依据。
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