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<p>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<sup>+</sup> cells leads to accelerated CML progression. Collectively, Gremlin 1 and Gremlin 1<sup>+</sup> cells are key defensive niche components in the spleen that limit CML progression, revealing an unprecedented mechanism for the body to fight off leukemia.</p>

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

  • 期刊论文

  • 发表日期：

    2025年3月17日

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  • 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

摘要

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.