Chromosomal NUP98-PHF23 translocation is associated with an aggressive form of acute myeloid leukemia (AML) and poor survival rate. Here, we report the molecular mechanisms by which NUP98-PHF23 recognizes the histone mark H3K4me3 and is inhibited by small molecule compounds, including disulfiram that directly targets the PHD finger of PHF23 (PHF23PHD). Our data support a critical role for the PHD fingers of NUP98-PHF23, and related NUP98-KDM5A and NUP98-BPTF fusions in driving leukemogenesis, and demonstrate that blocking this interaction in NUP98-PHF23 expressing AML cells leads to cell death through necrotic and late apoptosis pathways. An overlap of NUP98-KDM5A oncoprotein binding sites and H3K4me3-positive loci at the Hoxa/b gene clusters and Meis1 in ChIP-seq, together with NMR analysis of the H3K4me3-binding sites of the PHD fingers from PHF23, KDM5A and BPTF, suggests a common PHD finger-dependent mechanism that promotes leukemogenesis by this type of NUP98 fusions. Our findings highlight the direct correlation between the abilities of NUP98-PHD finger fusion chimeras to associate with H3K4me3-enriched chromatin and leukemic transformation.

染色体 NUP98-PHF23 易位与急性髓性白血病 (AML) 的侵袭性形式和较差的生存率相关。在这里，我们报告了 NUP98-PHF23 识别组蛋白标记 H3K4me3 并被小分子化合物抑制的分子机制，包括直接靶向 PHF23 PHD 指 (PHF23PHD) 的双硫仑。我们的数据支持 NUP98-PHF23 的 PHD 指以及相关的 NUP98-KDM5A 和 NUP98-BPTF 融合在驱动白血病发生中的关键作用，并证明在表达 NUP98-PHF23 的 AML 细胞中阻断这种相互作用会导致细胞通过坏死和晚期死亡。凋亡途径。 ChIP-seq 中 Hoxa/b 基因簇和 Meis1 上的 NUP98-KDM5A 癌蛋白结合位点和 H3K4me3 阳性位点的重叠，以及来自 PHF23、KDM5A 和 BPTF 的 PHD 指的 H3K4me3 结合位点的 NMR 分析表明一种常见的 PHD 手指依赖性机制，通过此类 NUP98 融合促进白血病发生。我们的研究结果强调了 NUP98-PHD 指融合嵌合体与富含 H3K4me3 的染色质相关的能力与白血病转化之间的直接相关性。