2. Academic Validation
  3. BRAF inhibitors enhance erythropoiesis and treat anemia through paradoxical activation of MAPK signaling

BRAF inhibitors enhance erythropoiesis and treat anemia through paradoxical activation of MAPK signaling

  • Signal Transduct Target Ther. 2024 Dec 2;9(1):338. doi: 10.1038/s41392-024-02033-6.
Shunkang Wu # 1 2,  Yuelin Deng # 1 2,  Haobo Sun 3 4,  Xuewen Liu 3 4,  Shuo Zhou 1 2,  Hanxi Zhao 1,  Huan Li 1 2,  Fusheng Guo 2 5,  Qiuyu Yue 1 2,  Fan Wu 1 2,  Xinying Zhao 1 2,  Na Li 1 2,  Shicong Zhu 1 2,  Qi Hu 1 2,  Si Xie 1 2,  Jie Zheng 6,  Meng Lv 7,  Yuan Kong 7,  Xiao-Jun Huang 2 7,  Xiaoguang Lei 2 5,  Xiangmin Tong 8,  Xiaofei Gao 9 10,  Hsiang-Ying Lee 11 12 13
Affiliations

Affiliations

  • 1 The MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing, 100871, China.
  • 2 Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, 100871, China.
  • 3 School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China.
  • 4 Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China.
  • 5 Department of Chemical Biology, College of Chemistry and Molecular Engineering, Peking University, Beijing, 100871, China.
  • 6 Hematology Center, Beijing Key Laboratory of Pediatric Hematology Oncology; National Key Discipline of Pediatrics (Capital Medical University); Key Laboratory of Major Diseases in Children, Ministry of Education; Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China.
  • 7 Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, 100871, China.
  • 8 Department of Hematology, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang, China. tongxiangmin@163.com.
  • 9 School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China. gaoxiaofei@westlake.edu.cn.
  • 10 Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China. gaoxiaofei@westlake.edu.cn.
  • 11 The MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing, 100871, China. slee@pku.edu.cn.
  • 12 Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, 100871, China. slee@pku.edu.cn.
  • 13 Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, 100871, China. slee@pku.edu.cn.
  • # Contributed equally.
PMID: 39617757 DOI: 10.1038/s41392-024-02033-6
Abstract

Erythropoiesis is a crucial process in hematopoiesis, yet it remains highly susceptible to disruption by various diseases, which significantly contribute to the global challenges of anemia and blood shortages. Current treatments like erythropoietin (EPO) or glucocorticoids often fall short, especially for hereditary anemias such as Diamond-Blackfan anemia (DBA). To uncover new erythropoiesis-stimulating agents, we devised a screening system using primary human hematopoietic stem and progenitor cells (HSPCs). We discovered that BRaf inhibitors (BRAFi), commonly used to treat BRafV600E melanoma, can unexpectedly and effectively promote progenitor cell proliferation by temporarily delaying erythroid differentiation. Notably, these inhibitors exhibited pronounced efficacy even under cytokine-restricted conditions and in patient samples of DBA. Mechanistically, although these BRAFi inhibit the MAPK cascade in BRafV600E mutant cells, they paradoxically act as amplifiers in wild-type BRaf cells, potently enhancing the cascade. Furthermore, we found that while the oncogenic BRafV600E mutation disrupts hematopoiesis and erythropoiesis through AP-1 hyperactivation, BRAFi minimally impact HSPC self-renewal and differentiation. In vivo studies have shown that BRAFi can enhance human hematopoiesis and erythropoiesis in severe immunodeficient mouse models and alleviate anemia in the Rpl11 haploinsufficiency DBA model, as well as Other relevant anemia models. This discovery underscores the role of the MAPK pathway in hematopoiesis and positions BRAFi as a promising therapeutic option for improving hematopoietic reconstitution and treating anemias, including DBA.

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