Transferrin in combination with induction chemotherapy improves outcomes in mouse models of acute myeloid leukemia
Menée à l'aide de modèles murins de leucémie myéloïde aiguë, cette étude met en évidence l'intérêt d'un traitement combinant transferrine et chimiothérapie d'induction
Acute myeloid leukemia (AML) is an aggressive leukemia with high rates of chemoresistance and relapse. Patients with AML undergoing induction chemotherapy often have delayed erythropoietic recovery and febrile neutropenia. Infection is a leading cause of mortality in this population. There is an unmet need to improve disease-specific outcomes in patients with AML undergoing cytotoxic chemotherapy. AML, at diagnosis, is characterized by increased levels of circulating iron due to erythroid block and cell death, which is further aggravated upon intensive chemotherapy. We hypothesized that iron, particularly toxic non–transferrin-bound iron (NTBI), can be redistributed away from AML cells and bacteria into nonmalignant transferrin receptor (CD71)–expressing cells by administering exogenous iron-free apotransferrin (apoTF). Using mouse models of AML, we show that mice treated with human apoTF had decreased NTBI and increased bone marrow erythropoiesis and B cell responses. ApoTF treatment resulted in normalization of bone marrow blood vessels and reduction of lipid peroxidation in endothelial cells. Crucially, apoTF combined with chemotherapy resulted in a reduction of AML cells and in improved survival, which was dependent on adaptive immunity. We established a murine model of Escherichia coli sepsis in leukemic mice receiving chemotherapy. We show that apoTF administration increased the survival of E. coli–infected mice. Mechanistically, apoTF treatment decreased the levels of circulating C-C motif chemokine ligand 2 (CCL2) and interleukin-6 through reduced expression of CCL2 in lipopolysaccharide-polarized macrophages. Our results demonstrate an overall benefit of iron redistribution induced by transferrin in combination with cytotoxic chemotherapy in AML. Transferrin in combination with chemotherapy improves outcomes in preclinical AML. Patients with acute myeloid leukemia (AML) can experience resistance to chemotherapy and impaired erythropoietic recovery after treatment. Lopes et al. found that transferrin, an iron-binding protein, can be used to divert iron from AML cells and bacteria to transferrin receptor–expressing cells under conditions of preclinical AML chemotherapy in mice. Treated mice lived longer than control animals with AML and chemotherapy treatment alone. In a mouse model of sepsis, animals were less likely to die when treated with transferrin without iron bound (apoTF). Together, these results support further investigation into combining transferrin with anticancer therapies in AML. —Brandon Berry
Science Translational Medicine , résumé, 2026