論文 - 詳細
| RRC ID | 73030 |
|---|---|
| 著者 | Okuda H, Miyamoto R, Takahashi S, Kawamura T, Ichikawa J, Harada I, Tamura T, Yokoyama A. |
| タイトル | RNA-binding proteins of KHDRBS and IGF2BP families control the oncogenic activity of MLL-AF4. |
| ジャーナル | Nat Commun |
| Abstract |
Chromosomal translocation generates the MLL-AF4 fusion gene, which causes acute leukemia of multiple lineages. MLL-AF4 is a strong oncogenic driver that induces leukemia without additional mutations and is the most common cause of pediatric leukemia. However, establishment of a murine disease model via retroviral transduction has been difficult owning to a lack of understanding of its regulatory mechanisms. Here, we show that MLL-AF4 protein is post-transcriptionally regulated by RNA-binding proteins, including those of KHDRBS and IGF2BP families. MLL-AF4 translation is inhibited by ribosomal stalling, which occurs at regulatory sites containing AU-rich sequences recognized by KHDRBSs. Synonymous mutations disrupting the association of KHDRBSs result in proper translation of MLL-AF4 and leukemic transformation. Consequently, the synonymous MLL-AF4 mutant induces leukemia in vivo. Our results reveal that post-transcriptional regulation critically controls the oncogenic activity of MLL-AF4; these findings might be valuable in developing novel therapies via modulation of the activity of RNA-binding proteins. |
| 巻・号 | 13(1) |
| ページ | 6688 |
| 公開日 | 2022-11-5 |
| DOI | 10.1038/s41467-022-34558-1 |
| PII | 10.1038/s41467-022-34558-1 |
| PMID | 36335100 |
| PMC | PMC9637093 |
| MeSH | Animals Child Humans Leukemia* / genetics Mice Myeloid-Lymphoid Leukemia Protein / metabolism Oncogene Proteins, Fusion* / metabolism Oncogenes RNA-Binding Proteins / genetics Translocation, Genetic |
| IF | 12.121 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | News |
| 各媒体での言及数の合計 | 5 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | Ba/F3(RCB0805) |