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  3. scRNA-seq reveals an immune microenvironment and JUN-mediated NK cell exhaustion in relapsed T-ALL

scRNA-seq reveals an immune microenvironment and JUN-mediated NK cell exhaustion in relapsed T-ALL

  • Cell Rep Med. 2025 May 20;6(5):102098. doi: 10.1016/j.xcrm.2025.102098.
Yong Liu 1,  Zefan Du 1,  Lindi Li 2,  Junbin Huang 2,  Su Liu 2,  Bo Lu 3,  Yifei Duan 2,  Yucai Cheng 2,  Tianwen Li 2,  Jing Zhang 4,  Jiani Mo 5,  Yalin Yang 2,  Wengqing Wang 2,  Hailin Zou 6,  Tianqi Liang 2,  Meng Jiang 7,  Mo Yang 8,  Yun Chen 9,  Cheng Ouyang 10,  Chun Chen 11
Affiliations

Affiliations

  • 1 Pediatric Hematology Laboratory, Division of Hematology/Oncology, Department of Pediatrics, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen 518107, Guangdong, China; Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen 518107, Guangdong, China.
  • 2 Pediatric Hematology Laboratory, Division of Hematology/Oncology, Department of Pediatrics, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen 518107, Guangdong, China.
  • 3 Department of Haematology, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen 518107, Guangdong, China.
  • 4 Department of Thyroid and Breast Surgery, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong 510623, China.
  • 5 Department of Hematology, Affiliated Hospital of Guangdong Medical University (GDMU), Zhanjiang 524001, Guangdong, China.
  • 6 Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen 518107, Guangdong, China.
  • 7 School of Medicine, Sun Yat-sen University, Shenzhen 518107, Guangdong, China.
  • 8 Pediatric Hematology Laboratory, Division of Hematology/Oncology, Department of Pediatrics, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen 518107, Guangdong, China; Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen 518107, Guangdong, China; Department of Thyroid and Breast Surgery, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong 510623, China. Electronic address: yangm1091@126.com.
  • 9 Pediatric Hematology Laboratory, Division of Hematology/Oncology, Department of Pediatrics, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen 518107, Guangdong, China; Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen 518107, Guangdong, China. Electronic address: cheny653@mail.sysu.edu.cn.
  • 10 Pediatric Hematology Laboratory, Division of Hematology/Oncology, Department of Pediatrics, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen 518107, Guangdong, China. Electronic address: ouycheng@mail2.sysu.edu.cn.
  • 11 Pediatric Hematology Laboratory, Division of Hematology/Oncology, Department of Pediatrics, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen 518107, Guangdong, China. Electronic address: chenchun@mail.sysu.edu.cn.
PMID: 40306275 DOI: 10.1016/j.xcrm.2025.102098
Abstract

T cell acute lymphoblastic leukemia (T-ALL) is a heterogeneous disease characterized by a high relapse rate. By single-cell transcriptome analysis, we characterize the bone marrow immune microenvironment in patients with T-ALL, identifying 13 major cell clusters. These patients exhibited abnormally expanded hematopoietic stem cells (HSCs) and granulocyte-monocyte progenitors (GMPs), immunosuppressive traits in CD4+ T, CD8+ T, and natural killer (NK) cells. Subdividing CD4+ T cells reveal two subsets transitioning between T helper (Th)1/Th2, Annexin-A1 (ANXA1)-GATA3-CD4+ T, and ANXA1+GATA3+CD4+ T. Additionally, NK cells demonstrate exhaustion in the tumor microenvironment of patients with relapsed T-ALL, with JUN identified as a critical factor. Additionally, JUN is also highly expressed in T-ALL and is crucial for maintaining its proliferation. The JUN inhibitor exhibited successful lethality toward leukemia cells and ameliorated NK cell exhaustion in relapsed T-ALL cell line, as well as in cell-derived tumor xenograft (CDX), patient-derived tumor xenograft (PDX), and NOTCH1-mutant mouse models. In summary, our findings enhance the understanding of T-ALL relapse mechanisms and support the development of innovative immunotherapies for patients with relapsed T-ALL.

Keywords

JUN; NK cells; T cell acute lymphoblastic leukemia; immune exhaustion; single-cell RNA sequencing.

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