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

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.