Oncogenic role of RARG rearrangements in acute myeloid leukemia resembling acute promyelocytic leukemia
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 f...
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55047-7 |
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| author | 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 Ke Li |
| author_facet | 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 Ke Li |
| author_sort | Feng Wang |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-294ef13a0838400fb56b830bf72b8eee |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
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| series | Nature Communications |
| spelling | doaj-art-294ef13a0838400fb56b830bf72b8eee2025-01-19T12:30:39ZengNature PortfolioNature Communications2041-17232025-01-0116111910.1038/s41467-024-55047-7Oncogenic role of RARG rearrangements in acute myeloid leukemia resembling acute promyelocytic leukemiaFeng Wang0Luyao Zhao1Yun Tan2Xufeng Cen3Huan Gao4Huimin Jiang5Ying Liu6Yunxuan Li7Tingting Zhang8Chenxi Zhao9Ting Shi10Guilin Xu11Churan Wang12Jiong Hu13Xia Li14Ya-Zhen Qin15Kankan Wang16Hong-Hu Zhu17Ke Li18State 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 CollegeState 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 CollegeShanghai 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 MedicineLiangzhu Laboratory, Zhejiang UniversityMarine College, Shandong UniversityState 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 CollegeState 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 CollegeState 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 CollegeState 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 CollegeState 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 CollegeDepartment of Hematology, Beijing Chao-Yang Hospital, Capital Medical UniversityShanghai 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 MedicineShanghai 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 MedicineShanghai 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 MedicineMarine College, Shandong UniversityNational Clinical Research Center for Hematologic Disease, Peking University People’s Hospital, Peking University Institute of HematologyShanghai 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 MedicineDepartment of Hematology, Beijing Chao-Yang Hospital, Capital Medical UniversityState 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 CollegeAbstract 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.https://doi.org/10.1038/s41467-024-55047-7 |
| spellingShingle | 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 Ke Li Oncogenic role of RARG rearrangements in acute myeloid leukemia resembling acute promyelocytic leukemia Nature Communications |
| title | Oncogenic role of RARG rearrangements in acute myeloid leukemia resembling acute promyelocytic leukemia |
| title_full | Oncogenic role of RARG rearrangements in acute myeloid leukemia resembling acute promyelocytic leukemia |
| title_fullStr | Oncogenic role of RARG rearrangements in acute myeloid leukemia resembling acute promyelocytic leukemia |
| title_full_unstemmed | Oncogenic role of RARG rearrangements in acute myeloid leukemia resembling acute promyelocytic leukemia |
| title_short | Oncogenic role of RARG rearrangements in acute myeloid leukemia resembling acute promyelocytic leukemia |
| title_sort | oncogenic role of rarg rearrangements in acute myeloid leukemia resembling acute promyelocytic leukemia |
| url | https://doi.org/10.1038/s41467-024-55047-7 |
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