The RNA m6A Reader YTHDF1 Is Required for Acute Myeloid Leukemia Progression

N-6-methyladenosine (m(6)A), the most abundant modification in mRNAs, has been defined as a crucial modulator in the progression of acute myelogenous leukemia (AML). Identification of the key regulators of m(6)A modifications in AML could provide further insights into AML biology and uncover more effective therapeutic strategies for patients with AML. Here, we report overexpression of YTHDF1, an m(6)A reader protein, in human AML samples at the protein level with enrichment in leukemia stem cells (LSC). Where-as YTHDF1 was dispensable for normal hematopoiesis in mice, depletion of YTHDF1 attenuated self-renewal, proliferation, and leukemic capacity of primary human and mouse AML cells in vitro and in vivo. Mechanistically, YTHDF1 promoted the translation of cyclin E2 in an m(6)A-dependent manner. Structure-based virtual screening of FDA-approved drugs identified tegaserod as a potential YTHDF1 inhibitor. Tegaserod blocked the direct binding of YTHDF1 with m(6)A-modified mRNAs and inhibited YTHDF1-regulated cyclin E2 translation. Moreover, tegaserod reduced the viability of patient-derived AML cells in vitro and prolonged survival in patient-derived xenograft models. Together, our study defines YTHDF1 as an integral regulator of AML progression by regulating the expression of m(6)A-modified mRNAs, which might serve as a potential therapeutic target for AML. Significance: The m(6)A reader YTHDF1 is required for progres-sion of acute myelogenous leukemia and can be targeted with the FDA-approved drug tegaserod to suppress leukemia growth.

Automated summary

N-6-methyladenosine (m(6)A) has been identified as a crucial modulator in acute myelogenous leukemia (AML). The overexpression of YTHDF1, an m(6)A reader protein, in AML samples, especially in leukemia stem cells, promotes AML progression. Depletion of YTHDF1 attenuates self-renewal, proliferation, and leukemic capacity of AML cells and can be targeted by the FDA-approved drug tegaserod. Tegaserod inhibits the binding of YTHDF1 with m(6)A-modified mRNAs and reduces AML cell viability in vitro and prolongs survival in xenograft models.