Leukemic Environment Alters Neutrophils Worsening Disease Progression

Abstract Acute Myeloid Leukemia (AML) is the abnormal differentiation of hematopoietic stem cells in the bone marrow into malignant blasts. The leukemic marrow environment plays an important role during disease progression, by shaping the immune landscape interacting with these blasts. Mounting evidence suggests neutrophils are complicit within tumors by enhancing tumorigenesis and immunosuppression; however, little is known about how these cells contribute to AML even though neutrophils comprise half the marrow cellularity. Tumor-associated neutrophils are found in an overactivated state, constantly releasing pro-inflammatory cytokines and granular proteins to promote tumorigenesis. Therefore, we investigated the neutrophil phenotype in our AML chimeric mouse model. We observed neutrophils in AML were also in an activated state. More importantly, sorted leukemic-exposed neutrophils were more susceptible to degranulation upon stimulation. Next, our single-cell RNA data showed that neutrophils within the AML environment had higher expression of ELANE, a gene encoding neutrophil elastase (NE). Increased NE levels have been associated with increased tumor burden in many cancers. Although NE levels increase inflammation which drives tumorigenesis, it may also directly increase leukemic blast proliferation. By targeting neutrophils in our AML chimeric model using anti-Ly6G antibody, we found decreased frequency of leukemic blasts in the neutrophil depleted mice. Also, there was a reduced frequency of the Lin-ckit +CD16/32 +leukemic stem cells. We hypothesize that over-activated neutrophils drive AML progression in the BM by releasing NE, providing a new avenue for disease intervention.