2. Academic Validation
  3. S100A4 mediates the accumulation and functions of myeloid-derived suppressor cells via GP130/JAK2/STAT3 signaling in acute myeloid leukemia

S100A4 mediates the accumulation and functions of myeloid-derived suppressor cells via GP130/JAK2/STAT3 signaling in acute myeloid leukemia

  • Biochim Biophys Acta Mol Basis Dis. 2024 Sep 5;1871(1):167498. doi: 10.1016/j.bbadis.2024.167498.
Yuhui Peng 1,  Jian Zhang 1,  Ting Zhang 1,  Chanjuan Wang 1,  Jingdi Bai 2,  Yi Li 1,  Juanjuan Duan 1,  Daogui Fan 1,  Wenli Fu 1,  Xinming Liang 1,  Xin Xie 1,  Xiaolan Qi 1,  Wei Hong 1,  Yan He 1,  ChangXue Wu 1,  Jing Zhou 1,  Pingping Chen 1,  Hongmei Zeng 1,  Yun Dai 3,  Wenfeng Yu 4,  Hua Bai 5,  Pengxiang Guo 6,  Zhu Zeng 7,  Qifang Zhang 8
Affiliations

Affiliations

  • 1 Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education & Key Laboratory of Medical Molecular Biology of Guizhou Province, School of Basic Medical Science, Guizhou Medical University, Guiyang 550004, Guizhou, China.
  • 2 The second hospital of Tianjin Medical University, Tianjin 300211, China.
  • 3 Laboratory of Cancer Precision Medicine, the First Hospital of Jilin University, 519 Dongminzhu Street, Changchun 130061, Jinlin, China.
  • 4 Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education & Key Laboratory of Medical Molecular Biology of Guizhou Province, School of Basic Medical Science, Guizhou Medical University, Guiyang 550004, Guizhou, China; Key Laboratory of Human Brain bank for Functions and Diseases of Department of Education of Guizhou Province, College of Basic Medical, Guizhou Medical University, Guiyang 550025, China.
  • 5 Medical Laboratory Center, the Third Affiliated Hospital of Guizhou Medical University, Duyun 558000, Guizhou, China.
  • 6 Department of Hematology, Guizhou Provincial People's Hospital, Guizhou University, Guiyang 550002, Guizhou, China. Electronic address: gygpx118@sina.com.
  • 7 School of Biology and Engineering, Guizhou Medical University, Guiyang 550004, Guizhou, China. Electronic address: 45203384@qq.com.
  • 8 Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education & Key Laboratory of Medical Molecular Biology of Guizhou Province, School of Basic Medical Science, Guizhou Medical University, Guiyang 550004, Guizhou, China; Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Guiyang 550004, Guizhou, China. Electronic address: 1507295114@qq.com.
PMID: 39243827 DOI: 10.1016/j.bbadis.2024.167498
Abstract

Background: Acute myeloid leukemia (AML) is an immunosuppressive hematologic malignancy with a poor prognosis. An immunosuppressive microenvironment blunts AML therapy. However, the prognostic and therapeutic roles of the factors that mediate immunosuppression in AML remain elusive.

Methods: S100 calcium-binding protein A4 (S100A4) was identified as an immunosuppression-mediating factor by analyzing The Cancer Genome Atlas AML project (TCGA-LAML) transcriptome data and data from AML-bearing mice and AML patients. The S100A4-mediated signaling pathway in myeloid-derived suppressor cells (MDSCs) was evaluated.

Results: Elevated S100A4 expression was positively associated with worse survival of AML patients, MDSCs, macrophages and immune checkpoints. S100A4 silencing downregulated the expression levels of MDSC-associated CD14, CCR2 and CCL2, reduced MDSC expansion and impaired MDSC-mediated inhibition of T cell activation and proliferation. S100A4-based prognostic signature (SPS) was an independent risk factor for AML patients. The high-risk group based on SPS was not only associated with adverse survival, MDSCs and macrophages and immune checkpoints but also insensitive to 25 chemotherapy drugs. It was also found that CCAAT enhancer binding protein beta (CEBPB) mediated S100A4 transcription. CEBPB silencing downregulated the expression levels of MDSC-associated CD14, CCR2 and CCL2. Mechanistically, S100A4 activated GP130/JAK2/STAT3 signaling in MDSCs by interacting with the cytokine-binding domain of GP130. Moreover, S100A4 mediated MDSC expansion through JAK2/STAT3 signaling.

Conclusion: This study uncovers the critical role of S100A4 in MDSC accumulation, and S100A4-based prognostic signature may guide chemotherapy sensitivity in patients with AML.

Keywords

Acute myeloid leukemia; GP130; Myeloid-derived suppressor cell; S100A4; STAT3.

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