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

Author

Listed:
  • Hiroshi Okuda

    (National Cancer Center
    Yokohama City University Graduate School of Medicine)

  • Ryo Miyamoto

    (National Cancer Center)

  • Satoshi Takahashi

    (National Cancer Center
    Kyoto University Graduate School of Medicine)

  • 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
    Yokohama City University)

  • Akihiko Yokoyama

    (National Cancer Center
    National Cancer Center Research Institute)

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.

Suggested Citation

  • Hiroshi Okuda & Ryo Miyamoto & Satoshi Takahashi & Takeshi Kawamura & Juri Ichikawa & Ibuki Harada & Tomohiko Tamura & Akihiko Yokoyama, 2022. "RNA-binding proteins of KHDRBS and IGF2BP families control the oncogenic activity of MLL-AF4," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34558-1
    DOI: 10.1038/s41467-022-34558-1
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