Academic Journal
RNA-binding protein RBM5 plays an essential role in acute myeloid leukemia by activating the oncogenic protein HOXA9
| العنوان: | RNA-binding protein RBM5 plays an essential role in acute myeloid leukemia by activating the oncogenic protein HOXA9 |
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| المؤلفون: | Mengli Zhang, Judith Hyle, Xiaowen Chen, Ye Xin, Yingcai Jin, Jianxiang Zhang, Xue Yang, Xinfeng Chen, Shaela Wright, Zhenling Liu, Wojciech Rosikiewicz, Beisi Xu, Liusheng He, Hong Liu, Nana Ping, Depei Wu, Feiqiu Wen, Chunliang Li, Peng Xu |
| المصدر: | Genome Biology, Vol 25, Iss 1, Pp 1-29 (2024) |
| بيانات النشر: | BMC, 2024. |
| سنة النشر: | 2024 |
| المجموعة: | LCC:Biology (General) LCC:Genetics |
| مصطلحات موضوعية: | CRISPR screen, Genome editing, RBM5, HOXA9, Acute myeloid leukemia, Biology (General), QH301-705.5, Genetics, QH426-470 |
| الوصف: | Abstract Background The oncogenic protein HOXA9 plays a critical role in leukemia transformation and maintenance, and its aberrant expression is a hallmark of most aggressive acute leukemia. Although inhibiting the upstream regulators of HOXA9 has been proven as a significant therapeutic intervention, the comprehensive regulation network controlling HOXA9 expression in leukemia has not been systematically investigated. Results Here, we perform genome-wide CRISPR/Cas9 screening in the HOXA9-driven reporter acute leukemia cells. We identify a poorly characterized RNA-binding protein, RBM5, as the top candidate gene required to maintain leukemia cell fitness. RBM5 is highly overexpressed in acute myeloid leukemia (AML) patients compared to healthy individuals. RBM5 loss triggered by CRISPR knockout and shRNA knockdown significantly impairs leukemia maintenance in vitro and in vivo. Through domain CRISPR screening, we reveal that RBM5 functions through a noncanonical transcriptional regulation circuitry rather than RNA splicing, such an effect depending on DNA-binding domains. By integrative analysis and functional assays, we identify HOXA9 as the downstream target of RBM5. Ectopic expression of HOXA9 rescues impaired leukemia cell proliferation upon RBM5 loss. Importantly, acute protein degradation of RBM5 through auxin-inducible degron system immediately reduces HOXA9 transcription. Conclusions We identify RBM5 as a new upstream regulator of HOXA9 and reveal its essential role in controlling the survival of AML. These functional and molecular mechanisms further support RBM5 as a promising therapeutic target for myeloid leukemia treatment. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 1474-760X |
| Relation: | https://doaj.org/toc/1474-760X |
| DOI: | 10.1186/s13059-023-03149-8 |
| URL الوصول: | https://doaj.org/article/26d5519bd45f4d089483909374e268f8 |
| رقم الانضمام: | edsdoj.26d5519bd45f4d089483909374e268f8 |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 1474760X |
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| DOI: | 10.1186/s13059-023-03149-8 |