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- W4308291421 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." @default.
- W4308291421 created "2022-11-10" @default.
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- W4308291421 date "2022-11-05" @default.
- W4308291421 modified "2023-10-14" @default.
- W4308291421 title "RNA-binding proteins of KHDRBS and IGF2BP families control the oncogenic activity of MLL-AF4" @default.
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- W4308291421 doi "https://doi.org/10.1038/s41467-022-34558-1" @default.
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