The RNA m6A reader YTHDF1 promotes hematopoietic malignancy by maintaining oncogenic translation

Abstract: N6-methyladenosine (m6A), the most abundant modification in mRNAs, has been defined as a crucial modulator in the progression of acute myeloid leukemia (AML) AML),while the detailed mechanism remains elusive . Here we report that YTHDF1 an m6A reader protein is overexpressed in human AML samples at the protein level with enrichment in leukemia stem cells (LSCs) LSCs). Whereas YTHDF1 is dispensable for normal hematopoiesis in mice depletion of YTHDF1 attenuates self renewal and proliferation of patient derived LSCs, and impedes leukemia establishment in immunodeficient mice. Mechanistically, YTHDF1 promotes the translation of diverse m 6 A modified oncogene mRNAs particularly cyclin E2. We applied a structure based virtual screening of FDA approved drugs and identified tegaserod as a potential YTHDF1 inhibitor. Tegaserod blocks the direct binding of YTHDF1 with m6A modified mRNAs and inhibits YTHDF1 regulated mRNA translation. Moreover, tegaserod inhibits leukemogenesis in vitro and in mice, phenocopying the loss of YTHDF1. Together, our study defines YTHDF1 as an integral regulator of AML progression at the translational level and identifies tegaserod as a potential therapeutic agent for AML by targeting YTHDF1.