Wang Feng, Zhao Luyao, Tan Yun, Cen Xufeng, Gao Huan, Jiang Huimin, Liu Ying, Li Yunxuan, Zhang Tingting, Zhao Chenxi, Shi Ting, Xu Guilin, Wang Churan, Hu Jiong, Li Xia, Qin Ya-Zhen, Wang Kankan, Zhu Hong-Hu, Li Ke
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Nat Commun. 2025 Jan 13;16(1):617. doi: 10.1038/s41467-024-55047-7.
Acute myeloid leukemia (AML) featuring retinoic acid receptor-gamma (RARG) rearrangements exhibits morphological features resembling those of acute promyelocytic leukemia but is associated with drug resistance and poor clinical outcomes. However, the mechanisms underlying the role of RARG fusions in leukemogenesis remain elusive. Here, we show that RARG fusions disrupt myeloid differentiation and promote proliferation and self-renewal of hematopoietic stem and progenitor cells (HSPCs) by upregulating BCL2 and ATF3. RARG fusions overexpression leads to preleukemic phenotypes but fails to induce oncogenic transformation. However, the co-occurrence of RARG fusions and heterozygous Wt1 loss induce fully penetrant AML by activating MYC and HOXA9/MEIS1 targets. Leveraging Connectivity Map resources and high-throughput screening, we identify venetoclax, homoharringtonine, and daunorubicin as potential therapeutic options for RARG-AML. Overall, our findings provide pivotal insights into the molecular mechanisms governed by RARG fusions and enhanced by WT1 loss in AML development and propose a rational therapeutic strategy for RARG-AML.
具有视黄酸受体γ（RARG）重排的急性髓系白血病（AML）表现出与急性早幼粒细胞白血病相似的形态学特征，但与耐药性及不良临床预后相关。然而，RARG融合在白血病发生中作用的潜在机制仍不清楚。在此，我们表明RARG融合通过上调BCL2和ATF3破坏髓系分化，并促进造血干细胞和祖细胞（HSPCs）的增殖和自我更新。RARG融合的过表达导致白血病前期表型，但未能诱导致癌转化。然而，RARG融合与野生型1（Wt1）杂合缺失同时出现，通过激活MYC和HOXA9/MEIS1靶点诱导完全显性的AML。利用连通图资源和高通量筛选，我们确定维奈克拉、高三尖杉酯碱和柔红霉素为RARG-AML的潜在治疗选择。总体而言，我们的研究结果为AML发生过程中由RARG融合控制并因Wt1缺失而增强的分子机制提供了关键见解，并为RARG-AML提出了合理的治疗策略。
