Liu Tianhui, Wang Tanzhen, Qi Lijuan, Liu Yujie, Shan Meng, Wang Fuqiang, Fang Yanglan, Liu Sining, Wen Lijun, Chen Suning, Wu Depei, Xu Yang
National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China.
Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, 215000, China.
Nat Commun. 2025 Jan 13;16(1):616. doi: 10.1038/s41467-024-54860-4.
Acute myeloid leukemia (AML) with retinoic acid receptor gamma (RARG) fusions, which exhibits clinical features resembling acute promyelocytic leukemia (APL), has been identified as a new subtype with poor clinical outcomes. The underlying mechanism of RARG-fusion leukemia remains poorly understood, and needs to be explored urgently to instruct developing effective therapeutic strategies. Here, using the most prevalent RARG fusion, CPSF6-RARG (CR), as a representative, we reveal that the CR fusion, enhances the expansion of myeloid progenitors, impairs their maturation and synergizes with RAS mutations to drive more aggressive myeloid malignancies. Mechanistically, CR fusion interacts with histone deacetylase 3 (HDAC3) to suppress expression of genes associated with myeloid differentiation including the myeloid transcription factor PU.1. Disrupting CR-HDAC3 interaction, restores PU.1 expression and myeloid differentiation. Furthermore, HDAC inhibitors effectively suppress CR-driven leukemia in vitro and in vivo. Hence, our data reveals the molecular bases of oncogenic CR fusion and provides a potential therapeutic approach against AML with CR fusion.
具有视黄酸受体γ（RARG）融合的急性髓系白血病（AML）表现出类似于急性早幼粒细胞白血病（APL）的临床特征，已被确定为一种临床预后较差的新亚型。RARG融合白血病的潜在机制仍知之甚少，迫切需要探索以指导制定有效的治疗策略。在此，我们以最常见的RARG融合体CPSF6-RARG（CR）为代表，揭示CR融合增强了髓系祖细胞的扩增，损害了它们的成熟，并与RAS突变协同作用，驱动更具侵袭性的髓系恶性肿瘤。从机制上讲，CR融合与组蛋白去乙酰化酶3（HDAC3）相互作用，抑制包括髓系转录因子PU.1在内的与髓系分化相关基因的表达。破坏CR-HDAC3相互作用可恢复PU.1表达和髓系分化。此外，HDAC抑制剂在体外和体内均能有效抑制CR驱动的白血病。因此，我们的数据揭示了致癌性CR融合的分子基础，并提供了一种针对具有CR融合的AML的潜在治疗方法。
