A Gremlin 1-expressing splenic niche cell population restrains chronic myeloid leukemia by antagonizing the BMP pathway PMID: 40097655

ADC Targets in Oncology

2026-04-10

A Gremlin 1-expressing splenic niche cell population restrains chronic myeloid leukemia by antagonizing the BMP pathway

Nat Cancer. 2025 Apr;6(4):666-681. doi: 10.1038/s43018-025-00933-2.

Jinming Wang ^# ¹ , Penghui Xu ^# ¹ , Zhongzhong Ji ¹ , Chaping Cheng ¹ , Yiyun Liu ¹ , Genyu Du ¹ , Shilei Zhang ² , Juju Miao ¹ , Deng Wang ¹ , Ruoyang Chen ³ , Dawei Li ³ , Kai Zhang ¹ , Huifang Zhao ¹ , Yujiao Sun ¹ , Xinyu Chen ¹ , Na Jing ¹ , Kaiyuan Liu ¹ , Yuman He ¹ , Xialian Xi ¹ , Yingchao Zhang ¹ , Nan Wang ¹ , Longmei Xu ⁴ , Jufang Yao ⁵ , Xiaomei Gao ⁶ , Jianhua Zhou ⁶ , Songqing Fan ⁷ , Xiaorui Wang ⁸ , Shuxian Dong ⁹ , Fangli Chen ¹⁰ , Jian Hou ¹¹ , Ming Zhang ³ , Wei-Qiang Gao ¹ , Lijing Shen ¹¹ , Pengcheng Zhang ¹² , Helen He Zhu ¹³

Affiliations

1. State Key Laboratory of Systems Medicine for Cancer, Renji-Med-X Stem Cell Research Center, Department of Urology, Ren Ji Hospital, Shanghai Cancer Institute, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.
2. Department of Pathology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
3. Department of Urology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
4. Shanghai Cancer Institute, Shanghai, China.
5. Animal Facility of Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
6. Department of Pathology, Xiangya Hospital, Central South University, Changsha, China.
7. Department of Pathology, the Second Xiangya Hospital, Central South University, Changsha, China.
8. Clinical Laboratory Medicine Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
9. Precision Research Center for Refractory Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
10. Department of Hematology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
11. Department of Hematology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
12. School of Biomedical Engineering, ShanghaiTech University, Shanghai, China.
13. State Key Laboratory of Systems Medicine for Cancer, Renji-Med-X Stem Cell Research Center, Department of Urology, Ren Ji Hospital, Shanghai Cancer Institute, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China. [email protected].
# Contributed equally.

Abstract

The spleen plays a critical role in the pathogenesis of leukemia. However, our understanding of the splenic niche is very limited. Herein, we report that induced expression of the secreted protein Gremlin 1 in a mouse model restrains chronic myeloid leukemia (CML) progression and synergizes with tyrosine kinase inhibitor treatment, whereas blockade of Gremlin 1 promotes CML development. Intriguingly, the effect of Gremlin 1 is most evident in the spleen but not in the bone marrow. Gremlin 1 induces Apoptosis of leukemic stem cells via antagonizing the BMP pathway. Single-cell RNA Sequencing and experimental validation together show that Gremlin 1 marks a unique stromal cell population in the spleens of both mice and humans. Genetic ablation of Gremlin 1⁺ cells leads to accelerated CML progression. Collectively, Gremlin 1 and Gremlin 1⁺ cells are key defensive niche components in the spleen that limit CML progression, revealing an unprecedented mechanism for the body to fight off leukemia.