Apotransferrin combined with chemotherapy reduces AML cells and improves survival in mouse models by redistributing iron.
Background
Acute myeloid leukemia (AML) is an aggressive blood cancer marked by high chemoresistance and relapse. Patients undergoing induction chemotherapy often suffer delayed erythropoietic recovery and febrile neutropenia, with infection being a leading cause of mortality. A critical unmet need exists to improve disease outcomes. AML is characterized by increased circulating iron, especially toxic non-transferrin-bound iron (NTBI), which is exacerbated by intensive chemotherapy. This study hypothesized that exogenous iron-free apotransferrin (apoTF) could redistribute iron away from AML cells and bacteria into nonmalignant CD71-expressing cells.
Study Design
Researchers utilized mouse models of AML to investigate the effects of human apoTF in combination with induction chemotherapy. Mice were treated with human apoTF alongside standard cytotoxic chemotherapy. To assess infection outcomes, a murine model of Escherichia coli sepsis was established in leukemic mice receiving chemotherapy. Key endpoints included levels of NTBI, bone marrow erythropoiesis, B cell responses, AML cell reduction, survival rates, endothelial lipid peroxidation, and circulating CCL2 and IL-6 levels.
Results
Mice treated with human apoTF demonstrated decreased levels of toxic non-transferrin-bound iron (NTBI). This treatment also led to increased bone marrow erythropoiesis and enhanced B cell responses. Furthermore, apoTF normalized bone marrow blood vessels and reduced 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. In a model of
E. colisepsis, apoTF administration significantly increased the survival of infected leukemic mice. Mechanistically, apoTF treatment decreased circulating levels ofC-C motif chemokine ligand 2 (CCL2)andinterleukin-6 (IL-6)by reducingCCL2expression in lipopolysaccharide-polarized macrophages.
Key Findings
- Apotransferrin decreased toxic non-transferrin-bound iron (NTBI).
- Apotransferrin increased bone marrow erythropoiesis and B cell responses.
- Apotransferrin combined with chemotherapy reduced AML cells and improved survival.
- Apotransferrin increased survival in
E. coli-infected leukemic mice. - Apotransferrin decreased circulating
CCL2andIL-6levels.
Why It Matters
Apotransferrin presents a promising adjunctive strategy to improve outcomes in AML patients undergoing chemotherapy. This approach addresses critical challenges like chemoresistance, infection susceptibility, and delayed hematopoietic recovery by modulating iron metabolism and inflammation. By redistributing toxic iron and reducing pro-inflammatory cytokines like CCL2 and IL-6, apoTF could enhance the efficacy of chemotherapy and mitigate severe side effects. This preclinical data suggests a novel therapeutic avenue to improve overall survival and reduce treatment-related morbidity, warranting further investigation into human translation and optimal dosing protocols.
transferrin
apotransferrin
acute myeloid leukemia
aml
chemotherapy
iron metabolism