The USP7-TRIM27 axis as part of non-canonical PRC1.1 is a druggable target in leukemia

In an attempt to unravel the functionality and targettability of the non-canonical PRC1.1 Polycomb complex in human leukemogenesis, we dissected the subunit composition of the PRC1.1 complex and show that USP7 and TRIM27 are integral components. USP7 interactome analyses show that PRC1.1 is the predominant Polycomb complex co-precipitating with USP7. USP7 inhibition results in PRC1.1 disassembly and loss of chromatin binding, coinciding with reduced H2AK119ub and H3K27ac levels and diminished gene transcription of active PRC1.1-controlled loci, whereas H3K4me3 levels remain unaffected. TRIM27 and USP7 are reciprocally required for incorporation into PRC1.1, and TRIM27 knockdown partially rescues USP7 inhibitor sensitivity. USP7 inhibitors effectively impair proliferation in (primary) AML cells in vitro, also independent of the USP7-MDM2-TP53 axis, and MLL-AF9-induced leukemia is significantly delayed in vivo in human leukemia xenografts. We propose a model where USP7 counteracts TRIM27 E3 ligase activity, thereby maintaining PRC1.1 integrity and function. Moreover, USP7 inhibition may be a promising new strategy to treat AML patients.

为阐明人类白血病发生过程中非经典多梳抑制复合体1.1（PRC1.1）的功能与可靶向性，我们解析了该复合物的亚基组成，证实泛素特异性蛋白酶7（USP7）与三结构域蛋白27（TRIM27）为其核心组成成分。USP7相互作用组分析显示，PRC1.1是与USP7共沉淀的主要多梳复合物（Polycomb complex）。USP7抑制可导致PRC1.1解离并丧失染色质结合能力，同时伴随组蛋白H2A赖氨酸119位点泛素化（H2AK119ub）与组蛋白H3赖氨酸27位点乙酰化（H3K27ac）水平降低，以及PRC1.1调控的活跃基因座的转录水平下调，而组蛋白H3赖氨酸4位点三甲基化（H3K4me3）水平则不受影响。TRIM27与USP7对于彼此整合进入PRC1.1复合物存在相互依赖关系，且TRIM27基因敲低可部分挽救USP7抑制剂诱导的细胞敏感性。USP7抑制剂可在体外有效抑制原代急性髓系白血病（AML）细胞的增殖，且该效应不依赖于USP7-MDM2-TP53信号轴；在人白血病异种移植模型（xenografts）中，MLL-AF9融合基因诱导的白血病的发生可被显著延迟。我们提出了一个模型：USP7通过拮抗TRIM27的E3泛素连接酶活性，维持PRC1.1复合物的完整性与功能。此外，USP7抑制或可成为治疗AML患者的极具潜力的全新策略。