Loss of RNA-binding protein CELF2 promotes acute leukemia development via FAT10-mTORC1
© 2024. The Author(s)..
RNA-binding proteins (RBPs) are critical regulators for RNA transcription and translation. As a key member of RBPs, ELAV-like family protein 2 (CELF2) has been shown to regulate RNA splicing and embryonic hematopoietic development and was frequently seen dysregulated in acute myeloid leukemia (AML). However, the functional role(s) of CELF2 in hematopoiesis and leukemogenesis has not been fully elucidated. In the current study, we showed that Celf2 deficiency in hematopoietic system led to enhanced HSCs self-renewal and differentiation toward myeloid cells in mice. Loss of Celf2 accelerated myeloid cell transformation and AML development in MLL-AF9-induced AML murine models. Gene expression profiling integrated with RNA immunoprecipitation sequencing (RIP-Seq), together with biochemical experiments revealed that CELF2 deficiency stabilizes FAT10 mRNA, promotes FAT10 translation, thereby increases AKT phosphorylation and mTORC1 signaling pathway activation. Notably, combination therapy with a mTORC1 inhibitor (Rapamycin) and a MA9/DOTL1 inhibitor (EPZ-5676) reduced the leukemia burden in MLL-AF9 mice lacking Celf2 in vivo. Our study elucidated a novel mechanism by which the CELF2/FAT10-AKT/mTORC1 axis regulates the proliferation of normal blood cells and the development of AML, thus providing potential therapeutic targets for myeloid leukemia suppression.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2024 |
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| Enthalten in: |
Oncogene - (2024) vom: 21. März |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Guo, Tengxiao [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Revised 22.03.2024 published: Print-Electronic Citation Status Publisher |
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| doi: |
10.1038/s41388-024-03006-3 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM370044282 |
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| 245 | 1 | 0 | |a Loss of RNA-binding protein CELF2 promotes acute leukemia development via FAT10-mTORC1 |
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| 520 | |a © 2024. The Author(s). | ||
| 520 | |a RNA-binding proteins (RBPs) are critical regulators for RNA transcription and translation. As a key member of RBPs, ELAV-like family protein 2 (CELF2) has been shown to regulate RNA splicing and embryonic hematopoietic development and was frequently seen dysregulated in acute myeloid leukemia (AML). However, the functional role(s) of CELF2 in hematopoiesis and leukemogenesis has not been fully elucidated. In the current study, we showed that Celf2 deficiency in hematopoietic system led to enhanced HSCs self-renewal and differentiation toward myeloid cells in mice. Loss of Celf2 accelerated myeloid cell transformation and AML development in MLL-AF9-induced AML murine models. Gene expression profiling integrated with RNA immunoprecipitation sequencing (RIP-Seq), together with biochemical experiments revealed that CELF2 deficiency stabilizes FAT10 mRNA, promotes FAT10 translation, thereby increases AKT phosphorylation and mTORC1 signaling pathway activation. Notably, combination therapy with a mTORC1 inhibitor (Rapamycin) and a MA9/DOTL1 inhibitor (EPZ-5676) reduced the leukemia burden in MLL-AF9 mice lacking Celf2 in vivo. Our study elucidated a novel mechanism by which the CELF2/FAT10-AKT/mTORC1 axis regulates the proliferation of normal blood cells and the development of AML, thus providing potential therapeutic targets for myeloid leukemia suppression | ||
| 650 | 4 | |a Journal Article | |
| 700 | 1 | |a Wang, Yuxia |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Xiaolu |e verfasserin |4 aut | |
| 700 | 1 | |a Hou, Shuaibing |e verfasserin |4 aut | |
| 700 | 1 | |a Lan, Yanjie |e verfasserin |4 aut | |
| 700 | 1 | |a Yuan, Shengnan |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Shuang |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Fei |e verfasserin |4 aut | |
| 700 | 1 | |a Chu, Yajing |e verfasserin |4 aut | |
| 700 | 1 | |a Ma, Yuanwu |e verfasserin |4 aut | |
| 700 | 1 | |a Cheng, Tao |e verfasserin |4 aut | |
| 700 | 1 | |a Yu, Jia |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Bing |e verfasserin |4 aut | |
| 700 | 1 | |a Yuan, Weiping |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Xiaomin |e verfasserin |4 aut | |
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