CPSF6-RARγ interacts with histone deacetylase 3 to promote myeloid transformation in RARG-fusion acute myeloid leukemia
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 un...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-54860-4 |
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| author | Tianhui Liu Tanzhen Wang Lijuan Qi Yujie Liu Meng Shan Fuqiang Wang Yanglan Fang Sining Liu Lijun Wen Suning Chen Depei Wu Yang Xu |
| author_facet | Tianhui Liu Tanzhen Wang Lijuan Qi Yujie Liu Meng Shan Fuqiang Wang Yanglan Fang Sining Liu Lijun Wen Suning Chen Depei Wu Yang Xu |
| author_sort | Tianhui Liu |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-98cf616861bf476ea46fb8161428f9fe |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-98cf616861bf476ea46fb8161428f9fe2025-01-19T12:31:41ZengNature PortfolioNature Communications2041-17232025-01-0116111510.1038/s41467-024-54860-4CPSF6-RARγ interacts with histone deacetylase 3 to promote myeloid transformation in RARG-fusion acute myeloid leukemiaTianhui Liu0Tanzhen Wang1Lijuan Qi2Yujie Liu3Meng Shan4Fuqiang Wang5Yanglan Fang6Sining Liu7Lijun Wen8Suning Chen9Depei Wu10Yang Xu11National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow UniversityNational Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow UniversityNational Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow UniversityNational Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow UniversityNational Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow UniversitySuzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical CollegeNational Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow UniversityNational Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow UniversityNational Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow UniversityNational Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow UniversityNational Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow UniversityNational Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow UniversityAbstract 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.https://doi.org/10.1038/s41467-024-54860-4 |
| spellingShingle | Tianhui Liu Tanzhen Wang Lijuan Qi Yujie Liu Meng Shan Fuqiang Wang Yanglan Fang Sining Liu Lijun Wen Suning Chen Depei Wu Yang Xu CPSF6-RARγ interacts with histone deacetylase 3 to promote myeloid transformation in RARG-fusion acute myeloid leukemia Nature Communications |
| title | CPSF6-RARγ interacts with histone deacetylase 3 to promote myeloid transformation in RARG-fusion acute myeloid leukemia |
| title_full | CPSF6-RARγ interacts with histone deacetylase 3 to promote myeloid transformation in RARG-fusion acute myeloid leukemia |
| title_fullStr | CPSF6-RARγ interacts with histone deacetylase 3 to promote myeloid transformation in RARG-fusion acute myeloid leukemia |
| title_full_unstemmed | CPSF6-RARγ interacts with histone deacetylase 3 to promote myeloid transformation in RARG-fusion acute myeloid leukemia |
| title_short | CPSF6-RARγ interacts with histone deacetylase 3 to promote myeloid transformation in RARG-fusion acute myeloid leukemia |
| title_sort | cpsf6 rarγ interacts with histone deacetylase 3 to promote myeloid transformation in rarg fusion acute myeloid leukemia |
| url | https://doi.org/10.1038/s41467-024-54860-4 |
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