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  3. STING activation in TET2-mutated hematopoietic stem/progenitor cells contributes to the increased self-renewal and neoplastic transformation

STING activation in TET2-mutated hematopoietic stem/progenitor cells contributes to the increased self-renewal and neoplastic transformation

  • Leukemia. 2023 Oct 10. doi: 10.1038/s41375-023-02055-z.
Jiaying Xie # 1,  Mengyao Sheng # 1,  Shaoqin Rong # 1,  Dan Zhou # 2,  Chao Wang 3,  Wanling Wu 4,  Jingru Huang 1,  Yue Sun 1,  Yin Wang 1,  Pingyue Chen 1,  Yushuang Wu 1,  Yuanxian Wang 1,  Lan Wang 5,  Bo O Zhou 3,  Xinxin Huang 1,  Colum P Walsh 6 7,  Stefan K Bohlander 8,  Jian Huang 9 10,  Xiaoqin Wang 4,  Guo-Liang Xu 11 12,  Hai Gao 13,  Yuheng Shi 14 15
Affiliations

Affiliations

  • 1 Institutes of Biomedical Sciences, Shanghai Xuhui Central Hospital, Medical College of Fudan University, Chinese Academy of Medical Sciences (RU069), Shanghai, 200032, China.
  • 2 Center for Medical Research and Innovation, Shanghai Pudong Hospital, Institutes of Biomedical Sciences, Medical College of Fudan University, Shanghai, 201399, China.
  • 3 China State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, 200031, China.
  • 4 Department of Hematology, Huashan Hospital, Fudan University, Shanghai, 200024, China.
  • 5 CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, 200031, China.
  • 6 Genomic Medicine Research Group, Biomedical Sciences, Ulster University, Coleraine, BT52 1SA, UK.
  • 7 Centre for Research and Development, Region Gävleborg/Uppsala University, Gävle, Sweden.
  • 8 Leukaemia & Blood Cancer Research Unit, Department of Molecular Medicine and Pathology, The University of Auckland, Auckland, New Zealand.
  • 9 Coriell Institute for Medical Research, Camden, NJ, 08103, USA.
  • 10 Temple University Lewis Katz School of Medicine, Center for Metabolic Disease Research, Philadelphia, PA, 19140, USA.
  • 11 Institutes of Biomedical Sciences, Shanghai Xuhui Central Hospital, Medical College of Fudan University, Chinese Academy of Medical Sciences (RU069), Shanghai, 200032, China. [email protected].
  • 12 China State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, 200031, China. [email protected].
  • 13 Institutes of Biomedical Sciences, Shanghai Xuhui Central Hospital, Medical College of Fudan University, Chinese Academy of Medical Sciences (RU069), Shanghai, 200032, China. [email protected].
  • 14 Institutes of Biomedical Sciences, Shanghai Xuhui Central Hospital, Medical College of Fudan University, Chinese Academy of Medical Sciences (RU069), Shanghai, 200032, China. [email protected].
  • 15 Shanghai Key Laboratory of Clinical Geriatric Medicine, Shanghai, Huadong Hospital, Shanghai, 200040, China. [email protected].
  • # Contributed equally.
PMID: 37816954 DOI: 10.1038/s41375-023-02055-z
Abstract

Somatic loss-of-function mutations of the dioxygenase Ten-eleven translocation-2 (TET2) occur frequently in individuals with clonal hematopoiesis (CH) and acute myeloid leukemia (AML). These common hematopoietic disorders can be recapitulated in mouse models. However, the underlying mechanisms by which the deficiency in TET2 promotes these disorders remain unclear. Here we show that the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) pathway is activated to mediate the effect of TET2 deficiency in dysregulated hematopoiesis in mouse models. DNA damage arising in Tet2-deficient hematopoietic stem/progenitor cells (HSPCs) leads to activation of the cGAS-STING pathway which in turn promotes the enhanced self-renewal and development of CH. Notably, both pharmacological inhibition and genetic deletion of STING suppresses Tet2 mutation-induced aberrant hematopoiesis. In patient-derived xenograft (PDX) models, STING inhibition specifically attenuates the proliferation of leukemia cells from TET2-mutated individuals. These observations suggest that the development of CH associated with TET2 mutations is powered through chronic inflammation dependent on the activated cGAS-STING pathway and that STING may represent a potential target for intervention of relevant hematopoietic diseases.

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