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

IF 23.5 1区医学 Q1 ONCOLOGY Nature cancer Pub Date : 2025-03-17 DOI:10.1038/s43018-025-00933-2

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

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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.

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来源期刊

Nature cancer Medicine-Oncology

CiteScore

31.10

自引率

1.80%

发文量

129

期刊介绍： Cancer is a devastating disease responsible for millions of deaths worldwide. However, many of these deaths could be prevented with improved prevention and treatment strategies. To achieve this, it is crucial to focus on accurate diagnosis, effective treatment methods, and understanding the socioeconomic factors that influence cancer rates. Nature Cancer aims to serve as a unique platform for sharing the latest advancements in cancer research across various scientific fields, encompassing life sciences, physical sciences, applied sciences, and social sciences. The journal is particularly interested in fundamental research that enhances our understanding of tumor development and progression, as well as research that translates this knowledge into clinical applications through innovative diagnostic and therapeutic approaches. Additionally, Nature Cancer welcomes clinical studies that inform cancer diagnosis, treatment, and prevention, along with contributions exploring the societal impact of cancer on a global scale. In addition to publishing original research, Nature Cancer will feature Comments, Reviews, News & Views, Features, and Correspondence that hold significant value for the diverse field of cancer research.