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Targeting FTO Suppresses Cancer Stem Cell Maintenance and Immune Evasion.

Abstract

Fat mass and obesity-associated protein (FTO), an RNA N6-methyladenosine (m6A) demethylase, plays oncogenic roles in various cancers, presenting an opportunity for the development of effective targeted therapeutics. Here, we report two potent small-molecule FTO inhibitors that exhibit strong anti-tumor effects in multiple types of cancers. We show that genetic depletion and pharmacological inhibition of FTO dramatically attenuate leukemia stem/initiating cell self-renewal and reprogram immune response by suppressing expression of immune checkpoint genes, especially LILRB4. FTO inhibition sensitizes leukemia cells to T cell cytotoxicity and overcomes hypomethylating agent-induced immune evasion. Our study demonstrates that FTO plays critical roles in cancer stem cell self-renewal and immune evasion and highlights the broad potential of targeting FTO for cancer therapy.

Authors: Su R, Dong L, Li Y, Gao M, Han L, Wunderlich M, Deng X, Li H, Huang Y, Gao L, Li C, Zhao Z, Robinson S, Tan B, Qing Y, Qin X, Prince E, Xie J, Qin H, Li W, Shen C, Sun J, Kulkarni P, Weng H, Huang H, Chen Z, Zhang B, Wu X, Olsen MJ, Müschen M, Marcucci G
Journal: Cancer Cell. 2020 Jul 13;38(1):79-96
Year: 2020
PubMed: Find in PubMed