CPSF6-RARγ interacts with histone deacetylase 3 to promote myeloid transformation in RARG-fusion acute myeloid leukemia

IF 14.7 1区 综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES Nature Communications Pub Date : 2025-01-13 DOI:10.1038/s41467-024-54860-4
Tianhui Liu, Tanzhen Wang, Lijuan Qi, Yujie Liu, Meng Shan, Fuqiang Wang, Yanglan Fang, Sining Liu, Lijun Wen, Suning Chen, Depei Wu, Yang Xu
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Abstract

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.

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CPSF6-RARγ与组蛋白去乙酰化酶3相互作用促进rarg融合急性髓性白血病的髓细胞转化
急性髓性白血病(AML)伴视黄酸受体γ (RARG)融合,其临床特征与急性早幼粒细胞白血病(APL)相似,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尚不清楚,迫切需要探索以指导制定有效的治疗策略。本文以最常见的RARG融合CPSF6-RARG (CR)为代表,揭示了CR融合增强了髓系祖细胞的扩张,损害了它们的成熟,并与RAS突变协同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,抑制髓细胞分化相关基因的表达,包括髓细胞转录因子PU.1。破坏CR-HDAC3相互作用,恢复PU.1表达和髓细胞分化。此外,HDAC抑制剂在体外和体内均能有效抑制cr驱动型白血病。因此,我们的数据揭示了致癌CR融合的分子基础,并为CR融合治疗AML提供了一种潜在的治疗方法。
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来源期刊
Nature Communications
Nature Communications Biological Science Disciplines-
CiteScore
24.90
自引率
2.40%
发文量
6928
审稿时长
3.7 months
期刊介绍: Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.
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