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

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 (), Kankan Wang (), Hong-Hu Zhu () and Ke Li ()
Additional contact information
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
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
Ke Li: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: 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.

Date: 2025
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-024-55047-7 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-024-55047-7

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-024-55047-7

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().