Zhang Xingya, Li Minjun, Chen Yingqian, Liu Jiayi, Zhang Jianhua, Shao Chen, Deng Boyu, Zhang Jianing, Wang Tianrui, Cao Ji, Xu Xiaojun, He Qiaojun, Yang Bo, Shao Xuejing, Ying Meidan
Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
Nanhu Brain-computer Interface Institute, Hangzhou, China.
Leukemia. 2025 Jul 24. doi: 10.1038/s41375-025-02698-0.
RUNX1-rearranged leukemia is one of the most common subtypes of leukemia associated with genetic abnormalities. Although the majority of patients respond to chemotherapy, relapse and long-term adverse effects remain significant challenges. RUNX1 fusions, resulting from chromosomal rearrangements, are pivotal oncogenic drivers, with over 70 distinct variants identified. Therefore, elucidating their regulatory mechanisms may help to develop novel therapeutic strategies. Herein, we identify a universal deubiquitinase, USP6, that stabilizes RUNX1 fusion proteins with different partners. Importantly, USP6 is specifically upregulated in RUNX1-rearranged leukemia and strongly correlates with poor patient outcomes. Mechanistically, USP6 stabilizes RUNX1 fusions to facilitate the formation of phase separation, leading to robust transcriptional activation of the fusions. Depletion of USP6 dramatically inhibits proliferation and induces differentiation of RUNX1-rearranged leukemic cells. The marketed drug auranofin is identified as a potential USP6 inhibitor, which induces degradation of different RUNX1 fusions, further triggering myeloid differentiation and arresting xenograft tumor growth. Notably, auranofin exhibits selective therapeutic efficacy in patient-derived leukemia blasts from RUNX1-rearranged cases. Together, we not only uncover a new biological function of USP6 in regulating the transcriptional activity of RUNX1 fusions but also validate USP6 as a promising drug target and auranofin as a candidate therapy for RUNX1-rearranged leukemia.
RUNX1重排白血病是与基因异常相关的最常见白血病亚型之一。尽管大多数患者对化疗有反应，但复发和长期不良反应仍然是重大挑战。由染色体重排产生的RUNX1融合是关键的致癌驱动因素，已鉴定出70多种不同变体。因此，阐明其调控机制可能有助于开发新的治疗策略。在此，我们鉴定出一种通用的去泛素化酶USP6，它能稳定与不同伴侣结合的RUNX1融合蛋白。重要的是，USP6在RUNX1重排白血病中特异性上调，且与患者的不良预后密切相关。从机制上讲，USP6稳定RUNX1融合蛋白以促进相分离的形成，从而导致融合蛋白的强大转录激活。USP6的缺失显著抑制RUNX1重排白血病细胞的增殖并诱导其分化。已上市的药物金诺芬被鉴定为一种潜在的USP6抑制剂，它能诱导不同RUNX1融合蛋白的降解，进一步触发髓系分化并阻止异种移植肿瘤生长。值得注意的是，金诺芬在RUNX1重排病例的患者来源白血病母细胞中表现出选择性治疗效果。总之，我们不仅揭示了USP6在调节RUNX1融合蛋白转录活性方面的新生物学功能，还验证了USP6作为一个有前景的药物靶点以及金诺芬作为RUNX1重排白血病候选治疗药物的有效性。
