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N6-methyladenosine (m6A), 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 m6A 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 m6A reader protein, in human AML samples at the protein level with enrichment in leukemia stem cells (LSC). Whereas 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 m6A-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 m6A-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 m6A-modified mRNAs, which might serve as a potential therapeutic target for AML. Significance: The m6A reader YTHDF1 is required for progression of acute myelogenous leukemia and can be targeted with the FDA-approved drug tegaserod to suppress leukemia growth.

Silica nanoparticles (SiNPs) have been reported to induce pulmonary fibrosis (PF) with an unknown mechanism. Recently, the activation of autophagy, a lysosome-dependent cell degradation pathway, by SiNPs has been identified in alveolar epithelial cells (AECs). However, the underlying mechanism and the relevance of SiNPs-induced autophagy to the development of PF remain elusive. Here, we report that autophagy dysfunction and subsequent apoptosis in AECs are involved in SiNPs-induced PF. SiNPs engulfed by AECs enhance autophagosome accumulation and apoptosis both in vivo and in vitro. Mechanically, SiNPs block autophagy flux through impairing lysosomal degradation via acidification inhibition. Lysosomal reacidification by cyclic-3′,5′-adenosine monophosphate (cAMP) significantly enhances autophagic degradation and attenuate apoptosis. Importantly, enhancement of autophagic degradation by rapamycin protects AECs from apoptosis and attenuates SiNPs-induced PF in the mouse model. Altogether, our data demonstrate a repressive effect of SiNPs on lysosomal acidification, contributing to the decreased autophagic degradation in AECs, thus leading to apoptosis and subsequent PF. These findings may provide an improved understanding of SiNPs-induced PF and molecular targets to antagonize it.

N ⁶ -methyladenosine (m ⁶ A) is a fundamentally important RNA modification for gene regulation, whose function is achieved through m ⁶ A readers. However, whether and how m ⁶ A readers play regulatory roles during fruit ripening and quality formation remains unclear. Here, we characterized SlYTH2 as a tomato m ⁶ A reader protein and profiled the binding sites of SlYTH2 at the transcriptome-wide level. SlYTH2 undergoes liquid–liquid phase separation and promotes RNA–protein condensate formation. The target mRNAs of SlYTH2, namely m ⁶ A-modified SlHPL and SlCCD1B associated with volatile synthesis, are enriched in SlYTH2-induced condensates. Through polysome profiling assays and proteomic analysis, we demonstrate that knockout of SlYTH2 expedites the translation process of SlHPL and SlCCD1B , resulting in augmented production of aroma-associated volatiles. This aroma enrichment significantly increased consumer preferences for CRISPR-edited fruit over wild type. These findings shed light on the underlying mechanisms of m ⁶ A in plant RNA metabolism and provided a promising strategy to generate fruits that are more attractive to consumers.