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RNA-binding proteins of KHDRBS and IGF2BP families control the oncogenic activity of MLL-AF4
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RNA-binding proteins of KHDRBS and IGF2BP families control the oncogenic activity of MLL-AF4
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Journal Article
RNA-binding proteins of KHDRBS and IGF2BP families control the oncogenic activity of MLL-AF4
2022
Overview
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.
The establishment of a mouse model of MLL-AF4-induced leukaemia is a challenge as the introduction of fusion gene of human MLL-AF4 does not cause leukaemia in mice. Here the authors reveal that MLL-AF4 is post-transcriptionally regulated by RNA-binding proteins that inhibits MLL-AF4 translation, thus, hampering MLL-AF4-mediated leukemic transformation.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/106
/ 14
/ 38
/ 38/35
/ 38/39
/ 38/71
/ 82/58
/ 82/80
/ Animals
/ Binding
/ Child
/ Humanities and Social Sciences
/ Humans
/ Leukemia
/ Mice
/ Mutation
/ Myeloid-Lymphoid Leukemia Protein - metabolism
/ Oncogene Proteins, Fusion - metabolism
/ Proteins
/ Regulatory mechanisms (biology)
/ RNA
/ RNA-Binding Proteins - genetics
/ Science
/ Stalling
