Decoding m6A RNA methylome identifies PRMT6-regulated lipid transport promoting AML stem cell maintenance

Abstract

N⁶-methyladenosine (m⁶A) is a common chemical modification for mammalian mRNA and exhibits high dynamics in various biological processes. However, dynamics of m⁶A RNA methylome during leukemogenesis remains unknown. Here, we delineate a comprehensive m⁶A landscape during acute myeloid leukemia (AML) development and identify PRMT6 as a key for maintaining AML stem cells. We observe an obvious change in m⁶A methylome during leukemogenesis and find that protein arginine methyltransferase PRMT6 and m⁶A reader IGF2BP2 maintain the function of human and murine leukemia stem cells (LSCs). Genetic deletion or pharmacological inhibition of PRMT6 damages AML development and LSC function. Mechanistically, IGF2BP2 stabilizes PRMT6 mRNA via m⁶A-mediated manner, which catalyzes H3R2me2a and suppresses lipid transporter MFSD2A expression. PRMT6 loss upregulates MFSD2A expression that increases docosahexaenoic acid levels and impairs LSC maintenance. Collectively, our findings reveal a critical role of PRMT6-MFSD2A signaling axis in AML development and provide a therapeutic strategy for targeting LSCs.

Keywords: IGF2BP2; PRMT6; RNA m(6)A; acute myeloid leukemia; leukemia stem cells.