Wang Jinming, Xu Penghui, Ji Zhongzhong, Cheng Chaping, Liu Yiyun, Du Genyu, Zhang Shilei, Miao Juju, Wang Deng, Chen Ruoyang, Li Dawei, Zhang Kai, Zhao Huifang, Sun Yujiao, Chen Xinyu, Jing Na, Liu Kaiyuan, He Yuman, Xi Xialian, Zhang Yingchao, Wang Nan, Xu Longmei, Yao Jufang, Gao Xiaomei, Zhou Jianhua, Fan Songqing, Wang Xiaorui, Dong Shuxian, Chen Fangli, Hou Jian, Zhang Ming, Gao Wei-Qiang, Shen Lijing, Zhang Pengcheng, Zhu Helen He
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.
Department of Pathology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Nat Cancer. 2025 Apr;6(4):666-681. doi: 10.1038/s43018-025-00933-2. Epub 2025 Mar 17.
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.
脾脏在白血病的发病机制中起着关键作用。然而，我们对脾生态位的了解非常有限。在此，我们报告在小鼠模型中诱导分泌蛋白Gremlin 1的表达可抑制慢性粒细胞白血病（CML）进展，并与酪氨酸激酶抑制剂治疗协同作用，而阻断Gremlin 1则促进CML发展。有趣的是，Gremlin 1的作用在脾脏中最为明显，而在骨髓中则不然。Gremlin 1通过拮抗骨形态发生蛋白（BMP）信号通路诱导白血病干细胞凋亡。单细胞RNA测序和实验验证共同表明，Gremlin 1标记了小鼠和人类脾脏中独特的基质细胞群。对Gremlin 1细胞进行基因消融会导致CML进展加速。总之，Gremlin 1和Gremlin 1细胞是脾脏中限制CML进展的关键防御性生态位成分，揭示了机体对抗白血病的前所未有的机制。
