Inflammation during hematological malignancies impairs neutrophil maturation and function through NFκΒ signaling 3473

Abstract Description Neutrophils are essential for defending against infections, however in cancer, they can be reprogrammed to support tumor growth. In acute myeloid leukemia (AML), the inflammatory microenvironment profoundly influences granulopoiesis. While the genetic mutations driving AML are well-characterized, their impact on bystander neutrophils—those exposed to AML cells but not mutated—has been less studied. Using a pre-clinical mouse model, where AML cells are transplanted into non-irradiated neutrophil reporter mice, we observed that neutrophils exposed to AML exhibited impaired granulopoiesis and acquired monocyte-like features. These AML-exposed neutrophils suppressed T-cell proliferation, demonstrating a potent immune-suppressive phenotype. Transcriptomic analysis revealed increased inflammation, degranulation, reduced chemotaxis, and elevated CD14 expression, a monocyte marker. Inflammatory cytokine profiling identified NFκB signaling as a critical pathway promoting CD14 expression. Clinically, neutrophils from AML patients exhibited similar granulopoiesis dysregulation with CD14 expression, implicating a new biomarker. These findings highlight a crucial translational implication: targeting AML-associated cytokines could restore neutrophil function and mitigate infection risk in patients. Our work underscores the role of AML-driven neutrophil dysfunction in immune suppression and suggests therapeutic strategies to enhance neutrophil responses during inflammation. Funding Sources National Institutes of Health grant R01HL150078 National Institutes of Health grant 1PO1HL131477 Mark Foundation Endeavor Award UAB T32 Training Program in Immunologic Diseases and Basic Immunology Topic Categories Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)