The oncomicropeptide APPLE promotes hematopoietic malignancy by enhancing translation initiation. Sun et al
Initiation is the rate-limiting step in translation, and its dysregulation is vital for carcinogenesis including hematopoietic malignancy. Thus, discovery of novel translation initiation regulators may provide promising therapeutic targets. Here, combining Ribo-seq, mass spectrometry and RNA-seq datasets, we discovered an oncomicropeptide, APPLE (a peptide located in ER), encoded by a noncoding RNA transcript in acute myeloid leukemia (AML). APPLE is overexpressed in various subtypes of AML and predicts a poor prognosis. The micropeptide is enriched in ribosomes and regulates the initiation step to enhance translation and to maintain high rates of oncoprotein synthesis. Mechanically, APPLE promotes PABPC1-eIF4G interaction, facilitates mRNA circularization and eIF4F initiation complex assembly to support a specific pro-cancer translation program. Targeting APPLE exhibited broad anti-cancer effects in vitro and in vivo. The study not only reports a previously unknown function of micropeptides, but also provides new opportunities for targeting the translation machinery in cancer cells.