FBXO3-mediated DUSP9 ubiquitination promotes leukemia stem cell maintenance and tyrosine kinase inhibitor resistance in chronic myeloid leukemia

  • Cell Rep Med. 2026 Mar 17;7(3):102686. doi: 10.1016/j.xcrm.2026.102686.
Xudong Li  1 ,  Shiyu Zuo  2 ,  Yanli Zhang  3 ,  Zexing Liu  4 ,  Na Shen  2 ,  Qingqing Ma  2 ,  Mingxia Sun  5 ,  Binglei Zhang  2 ,  Mengjia Li  2 ,  Hong Huang  2 ,  Mengya Gao  6 ,  Zhenghua Huang  2 ,  Huifang Zhao  3 ,  Yilin Chen  2 ,  Fengcai Gao  2 ,  Wenjuan Fan  2 ,  Zhen Zhang  7 ,  Yuhan Hu  2 ,  Yu An  2 ,  Siyue Li  2 ,  Miao Liu  4 ,  Yupeng Liu  2 ,  Yuxuan Liu  2 ,  Chaoge Li  2 ,  Yiguo Zhang  2 ,  Yingmei Li  2 ,  Weijie Cao  2 ,  Fang Wang  2 ,  Yongping Song  8 ,  Linping Xu  9 ,  Zhilei Bian  10 ,  Wei Li  11
Affiliations
  • 1. Department of Hematology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China; Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
  • 2. Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
  • 3. Department of Hematology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China.
  • 4. Department of Research and Foreign Affairs, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China.
  • 5. School of Public Health, Zhengzhou University, Zhengzhou, Henan 450000, China.
  • 6. Department of Hematology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China; Department of Research and Foreign Affairs, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China.
  • 7. Department of Abdominal and Pelvic Tumor Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, China.
  • 8. Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China. Electronic address: [email protected].
  • 9. Department of Research and Foreign Affairs, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China. Electronic address: [email protected].
  • 10. Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China; Institute of Infection and Immunity, Henan Academy of Innovations in Medical Science, Zhengzhou, China; State Key Laboratory of Metabolic Dysregulation & Prevention and Treatment of Esophageal Cancer, Zhengzhou, China. Electronic address: [email protected].
  • 11. Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China; Institute of Infection and Immunity, Henan Academy of Innovations in Medical Science, Zhengzhou, China; State Key Laboratory of Metabolic Dysregulation & Prevention and Treatment of Esophageal Cancer, Zhengzhou, China. Electronic address: [email protected].
PMID: 41850237 DOI: 10.1016/j.xcrm.2026.102686
Abstract

Eradicating leukemia stem cells (LSCs) and overcoming tyrosine kinase inhibitor (TKI) resistance is urgent for chronic myeloid leukemia (CML) treatment. We find that F-box protein 3 (Fbxo3) is highly upregulated in CD34+ CML stem cells from TKI-resistant patients and identify it as an innovative CML-LSC marker via single-cell RNA Sequencing (scRNA-seq). Fbxo3 deficiency induces Apoptosis and reduces proliferation of CML cell lines and LSCs in vitro and in vivo, with minimal effects on normal CD34+ hematopoietic stem cells (HSCs). Mechanistically, Fbxo3 interacts with DUSP9 to promote its ubiquitination and activate the MAPK pathway, critical for CML cell activity. DUSP9 knockdown partially reverses FBXO3-deficiency-mediated LSC elimination. Furthermore, Fbxo3 Inhibitor monotherapy or combination with imatinib effectively eradicates CML-LSCs, overcomes TKI resistance, and spares normal hematopoiesis. Collectively, our findings highlight FBXO3's role in CML progression and support combining Fbxo3 inhibitors with TKIs for durable LSC elimination.

Keywords
CML-LSCs; DUSP9; FBXO3; TKI resistance; chronic myeloid leukemia.
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