The acute myeloid leukemia microenvironment impairs neutrophil maturation and function through NF-κB signaling

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ABSTRACT: Acute myeloid leukemia (AML), an aggressive hematological malignancy, is driven by oncogenic mutations in stem and progenitor cells that give rise to AML blasts. Although these mutations are well characterized, their impact on healthy hematopoiesis, those blood cells exposed to AML but not mutated, has not been well characterized. Because the marrow is the major site for granulopoiesis, neutrophils are heavily influenced by AML pathobiology. Indeed, most patients with AML report neutropenia, rendering them susceptible to infections. However, because AML studies use peripheral blood mononuclear cells devoid of neutrophils, the characterization of neutrophil dysfunction remains poorly understood. To investigate AML-exposed neutrophils, a preclinical AML mouse model in which primary leukemic cells were transplanted into nonirradiated neutrophil reporter (Ly6G-tdTomato; Catchup) hosts was used. Neutrophils could not completely mature, suggesting impaired granulopoiesis. Single-cell transcriptomics of AML-exposed neutrophils revealed higher inflammation signatures and expression of CD14, an inflammatory marker. To address the factors contributing to this biology, an ex vivo cytokine screen was performed on marrow neutrophils, and it identified that nuclear factor κB signaling drove CD14 expression. AML-exposed neutrophils displayed widespread chromatin remodeling, and de novo motif discovery predicted increased binding sites for CCAAT enhancer-binding proteins and interferon regulatory factors. Moreover, AML-exposed neutrophils inhibited T-cell proliferation, highlighting their immune-suppressive capability. Finally, a similar biology of immature, inflammatory neutrophils was found in patients with AML, again indicating dysregulated granulopoiesis. Collectively, these data show that AML-associated inflammation alters neutrophil granulopoiesis, impairs neutrophil function, and drives immunosuppression, thereby contributing to patient susceptibility to infection.

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