| Autor: |
Hiroshi Okuda, Ryo Miyamoto, Satoshi Takahashi, Takeshi Kawamura, Juri Ichikawa, Ibuki Harada, Tomohiko Tamura, Akihiko Yokoyama |
| Rok vydání: |
2022 |
| Předmět: |
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| Zdroj: |
Nature Communications. 13 |
| ISSN: |
2041-1723 |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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