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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.

Hypoxia-inducible factor (HIF)-1␣ is a key nuclear transcription factor that regulates the cellular response to hypoxia, and is important for solid tumor growth and survival. However, the underlying role of HIF-1␣ in human chondrosarcoma has not been well characterized. This study aims to investigate the expression patterns of HIF-1␣ in chondrosarcoma, and its association with clinicopathologic features, Bcl-xL expression, apoptosis index (AI), and overall survival of patients with chondrosarcoma. Our results shown that the protein levels of HIF-1␣ were increased, and the mRNA and protein levels of Bcl-xL were also increased in SW1353 cells under hypoxic conditions. In eight patients with chondrosarcoma, increased expression of HIF-1␣ and Bcl-xL was detected in chondrosarcoma tissues compared with the paired adjacent normal tissues. Of 34 archival specimens of chondrosarcomas, 20 (58.8%) showed high HIF-1␣ protein expression as compared to benign cartilage tumors. Increased HIF-1␣ expression was correlated with a higher pathological grade and MSTS stage of chondrosarcoma. Moreover, HIF-1␣ expression was significantly associated with Bcl-xL expression and AI. More significantly, the survival rate of patients with HIF-1␣ high tumors was significantly lower than that of patients with HIF-1␣ low tumors. These findings suggest that increased HIF-1␣ levels mediated up-regulation of Bcl-xL play a prominent role in evasion of apoptosis and tumor progression, and can be predictive for the prognosis in human chondrosarcoma.