Saikosaponin D exhibits anti-leukemic activity by targeting FTO/m(6)A signaling

Purpose: The implementation of targeted therapies for acute myeloid leukemia (AML) has been challenging. Fat mass and obesity associated protein (FTO), an mRNA N(6)-methyladenosine (m(6)A) demethylase, functions as an oncogene that promotes leukemic oncogene-mediated cell transformation and leukemogenesis. Here, we investigated the role of Saikosaponin-d (SsD) in broad anti-proliferation effects in AML and evaluated the m(6)A demethylation activity by targeting FTO of SsD. Methods: It was examined whether and how SsD regulates FTO/m(6)A signaling in AML. The pharmacologic activities and mechanisms of actions of SsD in vitro, in mice, primary patient cells, and tyrosine kinase inhibitors-resistant cells were determined. Results: SsD showed a broadly-suppressed AML cell proliferation and promoted apoptosis and cell-cycle arrest both in vitro and in vivo. Mechanistically, SsD directly targeted FTO, thereby increasing global m(6)A RNA methylation, which in turn decreased the stability of downstream gene transcripts, leading to the suppression of relevant pathways. Importantly, SsD also overcame FTO/m(6)A-mediated leukemia resistance to tyrosine kinase inhibitors. Conclusion: Our findings demonstrated that FTO-dependent m(6)A RNA methylation mediated the anti-leukemic actions of SsD, thereby opening a window to develop SsD as an epitranscriptome-base drug for leukemia therapy.