FLT3L-based drug conjugate effectively targets chemoresistant leukemia stem cells in acute myeloid leukemia

  • Cell Rep Med. 2025 Sep 19:102365. doi: 10.1016/j.xcrm.2025.102365.
Dengyang Zhang  1 ,  Yao Guo  1 ,  Zhiyong Peng  2 ,  Yan Xiao  1 ,  Zhiguang Chang  1 ,  Liuting Yu  1 ,  Yuming Zhao  1 ,  Qi Zhang  1 ,  Lingling Ma  1 ,  Shuping Li  3 ,  Chi-Kong Li  4 ,  Kam Tong Leung  4 ,  Zhizhuang Joe Zhao  5 ,  Chun Chen  6 ,  Yun Chen  7
Affiliations
  • 1. Pediatric Hematology Laboratory, Division of Hematology/Oncology, Department of Pediatrics, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, Guangdong, China.
  • 2. Department of Hematology, Guangzhou First People's Hospital, Guangzhou, Guangdong, China.
  • 3. Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma, OK, USA.
  • 4. Department of Paediatrics, Hong Kong Hub of Paediatric Excellence, The Chinese University of Hong Kong, Shatin, Hong Kong, China.
  • 5. Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma, OK, USA. Electronic address: [email protected].
  • 6. Pediatric Hematology Laboratory, Division of Hematology/Oncology, Department of Pediatrics, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, Guangdong, China. Electronic address: [email protected].
  • 7. Pediatric Hematology Laboratory, Division of Hematology/Oncology, Department of Pediatrics, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, Guangdong, China. Electronic address: [email protected].
PMID: 40975063 DOI: 10.1016/j.xcrm.2025.102365
Abstract

Acute myeloid leukemia (AML) is a heterogeneous malignancy with poor prognosis due to relapse and chemotherapy resistance. FLT3 mutations promote AML and predict adverse outcomes. As most AML cells express FLT3, it represents a promising therapeutic target. In this study, we develop FL-Fc-DM1, a FLT3-targeted conjugate linking FLT3 ligand-Fc to DM1. FL-Fc-DM1 demonstrates potent anti-leukemic activity in vitro, ex vivo, and in both cell line- and patient-derived xenograft models. Notably, it effectively targets cytarabine-resistant AML cells by promoting cell cycle entry and inducing Apoptosis. FL-Fc-DM1 also significantly reduces functional leukemia stem cell frequency, as demonstrated by limiting dilution transplantation assays. The therapeutic efficacy can be further strengthened by BH3 mimetics. Importantly, toxicity assessments in a humanized mouse model show limited impact on normal human hematopoiesis at therapeutic doses. Our findings suggest that FL-Fc-DM1 is a promising candidate for AML treatment, even for cell cycle-arrested or slow-cycling chemo-resistant AML cells.

Keywords
AML; DM1; FLT3; FLT3L; cell cycle; chemotherapy resistance; ligand-drug conjugate.
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