RNA-binding proteins of KHDRBS and IGF2BP families control the oncogenic activity of MLL-AF4

Hiroshi Okuda (), Ryo Miyamoto, Satoshi Takahashi, Takeshi Kawamura, Juri Ichikawa, Ibuki Harada, Tomohiko Tamura and Akihiko Yokoyama ()
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Hiroshi Okuda: National Cancer Center
Ryo Miyamoto: National Cancer Center
Satoshi Takahashi: National Cancer Center
Takeshi Kawamura: The University of Tokyo
Juri Ichikawa: Yokohama City University Graduate School of Medicine
Ibuki Harada: Yokohama City University Graduate School of Medicine
Tomohiko Tamura: Yokohama City University Graduate School of Medicine
Akihiko Yokoyama: National Cancer Center

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-34558-1

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