2. Academic Validation
  3. FLT3L-based drug conjugate effectively targets chemoresistant leukemia stem cells in acute myeloid leukemia

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

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: joe-zhao@ouhsc.edu.
  • 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: chenchun@mail.sysu.edu.cn.
  • 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: cheny653@mail.sysu.edu.cn.
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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