| 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
|
| リソース情報 |
| ヒト・動物細胞 |
Ba/F3(RCB0805) |
