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Oncogenic role of RARG rearrangements in acute myeloid leukemia resembling acute promyelocytic leukemia

Author

Listed:
  • Feng Wang

    (Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Luyao Zhao

    (Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Yun Tan

    (Shanghai Jiao Tong University School of Medicine)

  • Xufeng Cen

    (Zhejiang University)

  • Huan Gao

    (Shandong University)

  • Huimin Jiang

    (Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Ying Liu

    (Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Yunxuan Li

    (Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Tingting Zhang

    (Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Chenxi Zhao

    (Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Ting Shi

    (Capital Medical University
    Chinese Institutes for Medical Research)

  • Guilin Xu

    (Shanghai Jiao Tong University School of Medicine)

  • Churan Wang

    (Shanghai Jiao Tong University School of Medicine)

  • Jiong Hu

    (Shanghai Jiao Tong University School of Medicine)

  • Xia Li

    (Shandong University)

  • Ya-Zhen Qin

    (Peking University People’s Hospital, Peking University Institute of Hematology)

  • Kankan Wang

    (Shanghai Jiao Tong University School of Medicine)

  • Hong-Hu Zhu

    (Capital Medical University
    Chinese Institutes for Medical Research)

  • Ke Li

    (Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College)

Abstract

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.

Suggested Citation

  • Feng Wang & Luyao Zhao & Yun Tan & Xufeng Cen & Huan Gao & Huimin Jiang & Ying Liu & Yunxuan Li & Tingting Zhang & Chenxi Zhao & Ting Shi & Guilin Xu & Churan Wang & Jiong Hu & Xia Li & Ya-Zhen Qin & , 2025. "Oncogenic role of RARG rearrangements in acute myeloid leukemia resembling acute promyelocytic leukemia," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-024-55047-7
    DOI: 10.1038/s41467-024-55047-7
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