RNA m^(6)A reader YTHDF2 facilitates precursor miR-126 maturation to promote acute myeloid leukemia progression

As the most common internal modification of mRNA,Ne-methyladenosine(m^(6)A)and its regulators modulate gene expression and play critical roles in various biological and patholog-ical processes including tumorigenesis.It was reported previously that m^(6)A methyltransferase(writer),methyltransferase-like 3(METTL3)adds m^(6)A in primary microRNAs(pri-miRNAs)and fa-cilitates its processing into precursor miRNAs(pre-miRNAs).However,it is unknown whether m^(6)A modification also plays a role in the maturation process of pre-miRNAs and(if so)whether such a function contributes to tumorigenesis.Here,we found that YTHDF2 is aberrantly overexpressed in acute myeloid leukemia(AML)patients,especially in relapsed patients,and plays an onco-genic role in AML.Moreover,YTHDF2 promotes expression of miR-126-3p(also known as miR-126,as it is the main product of precursor miR-126(pre-miR-126)),a miRNA that was reported as an oncomiRNA in AML,through facilitating the processing of pre-miR-126 into mature miR-126.Mechanistically,YTHDF2 recognizes m^(6)A modification in pre-miR-126 and recruits AGO2,a regulator of pre-miRNA processing,to promote the maturation of pre-miR-126.YTHDF2 posi-tively and negatively correlates with miR-126 and miR-126's downstream target genes,respec-tively,in AML patients,and forced expression of miR-126 could largely rescue YTHDF2/Ythdf2 depletion-mediated suppression on AML cell growth/proliferation and leukemogenesis,indi-cating that miR-126 is a functionally important target of YTHDF2 in AML.Overall,our studies not only reveal a previously unappreciated YTHDF2/miR-126 axis in AML and highlight the ther-apeutic potential of targeting this axis for AML treatment,but also suggest that m^(6)A plays a role in pre-miRNA processing that contributes to tumorigenesis.