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Targeting FTO Suppresses Cancer Stem Cell Maintenance and Immune Evasion.
Su, Rui; Dong, Lei; Li, Yangchan; Gao, Min; Han, Li; Wunderlich, Mark; Deng, Xiaolan; Li, Hongzhi; Huang, Yue; Gao, Lei; Li, Chenying; Zhao, Zhicong; Robinson, Sean; Tan, Brandon; Qing, Ying; Qin, Xi; Prince, Emily; Xie, Jun; Qin, Hanjun; Li, Wei; Shen, Chao; Sun, Jie; Kulkarni, Prakash; Weng, Hengyou; Huang, Huilin; Chen, Zhenhua; Zhang, Bin; Wu, Xiwei; Olsen, Mark J; Müschen, Markus; Marcucci, Guido; Salgia, Ravi; Li, Ling; Fathi, Amir T; Li, Zejuan; Mulloy, James C; Wei, Minjie; Horne, David; Chen, Jianjun.
Affiliation
  • Su R; Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA.
  • Dong L; Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA.
  • Li Y; Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; Department of Radiation Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
  • Gao M; Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; School of Pharmaceutical Science and Technology, Tianjin Key Laboratory for Modern Drug Delivery and High Efficiency, and Collaborative Innovation Center of Chemical Science and Engineer (Tianjin), Ti
  • Han L; Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; School of Pharmacy, China Medical University, Shenyang, Liaoning 110001, China.
  • Wunderlich M; Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
  • Deng X; Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA.
  • Li H; Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
  • Huang Y; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • Gao L; Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; Department of Pathology and Genomic Medicine, Houston Methodist, Houston, TX 77030, USA.
  • Li C; Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; Department of Hematology, The First Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang 31003, China.
  • Zhao Z; Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
  • Robinson S; Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA.
  • Tan B; Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA.
  • Qing Y; Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA.
  • Qin X; Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA.
  • Prince E; Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA.
  • Xie J; Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
  • Qin H; The Integrative Genomics Core, Beckman Research Institute, City of Hope Medical Center, Duarte, CA 91010, USA.
  • Li W; Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA.
  • Shen C; Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA.
  • Sun J; Department of Hematologic Malignancies Translational Science, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA.
  • Kulkarni P; Department of Medical Oncology and Therapeutics Research, City of Hope, Duarte, CA 91010, USA.
  • Weng H; Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA.
  • Huang H; Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA.
  • Chen Z; Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA.
  • Zhang B; Department of Hematologic Malignancies Translational Science, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; City of Hope Comprehensive Cancer Center and Gehr Family Center for Leukemia Research, City of Hope, Duarte, CA 91010, USA.
  • Wu X; The Integrative Genomics Core, Beckman Research Institute, City of Hope Medical Center, Duarte, CA 91010, USA.
  • Olsen MJ; Department of Pharmaceutical Sciences, College of Pharmacy-Glendale, Midwestern University, Glendale, AZ 85308, USA.
  • Müschen M; Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; City of Hope Comprehensive Cancer Center and Gehr Family Center for Leukemia Research, City of Hope, Duarte, CA 91010, USA.
  • Marcucci G; Department of Hematologic Malignancies Translational Science, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; City of Hope Comprehensive Cancer Center and Gehr Family Center for Leukemia Research, City of Hope, Duarte, CA 91010, USA.
  • Salgia R; Department of Medical Oncology and Therapeutics Research, City of Hope, Duarte, CA 91010, USA.
  • Li L; Department of Hematologic Malignancies Translational Science, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; City of Hope Comprehensive Cancer Center and Gehr Family Center for Leukemia Research, City of Hope, Duarte, CA 91010, USA.
  • Fathi AT; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
  • Li Z; Department of Pathology and Genomic Medicine, Houston Methodist, Houston, TX 77030, USA.
  • Mulloy JC; Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
  • Wei M; School of Pharmacy, China Medical University, Shenyang, Liaoning 110001, China.
  • Horne D; Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
  • Chen J; Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; City of Hope Comprehensive Cancer Center and Gehr Family Center for Leukemia Research, City of Hope, Duarte, CA 91010, USA. Electronic address: jianchen@coh.org.
Cancer Cell ; 38(1): 79-96.e11, 2020 07 13.
Article in En | MEDLINE | ID: mdl-32531268
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Enzyme Inhibitors / Immune Evasion / Cell Self Renewal / Alpha-Ketoglutarate-Dependent Dioxygenase FTO Limits: Humans Language: En Journal: Cancer Cell Journal subject: NEOPLASIAS Year: 2020 Document type: Article Affiliation country: United States
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Enzyme Inhibitors / Immune Evasion / Cell Self Renewal / Alpha-Ketoglutarate-Dependent Dioxygenase FTO Limits: Humans Language: En Journal: Cancer Cell Journal subject: NEOPLASIAS Year: 2020 Document type: Article Affiliation country: United States