Dynamic Changes in the Ability to Release Neutrophil ExtraCellular Traps in the Course of Childhood Acute Leukemias

Abstract

Acute leukemias, the most common cancers in children, are characterized by excessive proliferation of malignant progenitor cells. As a consequence of impaired blood cell production, leukemia patients are susceptible to infectious complications—a major cause of non-relapse mortality. Neutrophil extracellular traps (NETs) are involved in various pathologies, from autoimmunity to cancer. Although aberrant NETs formation may be partially responsible for immune defects observed in acute leukemia, still little is known on the NET release in the course of leukemia. Here, we present the first comprehensive evaluation of NETs formation by neutrophils isolated from children with acute leukemia in different stages of the disease and treatment stimulated in vitro with phorbol 12-myristate 13-acetate (PMA), N-formyl-methionyl-leucyl-phenylalanine (fMLP), and calcium ionophore (CI). NETs release was measured using quantitative fluorescent method and visualized microscopically. In this setting, NETs release was significantly impaired in leukemic children both at the diagnosis and during the treatment, and full restoration of neutrophil function was achieved only after successful completion of the leukemia treatment. We suggest that neutrophil function impairment may result from both disease- and treatment-related factors. In this context, deficient innate immune response observed in acute leukemia patients may be present regardless of neutrophil count and contribute to secondary immunodeficiency observed in this population.

Extracellular Traps Increase Burden of Bleeding by Damaging Endothelial Cell in Acute Promyelocytic Leukaemia

“…Immunofluorescence and flow cytometry showed that ETosis abilities of immature neutrophils were impaired in APL, while ETs secreted by mature neutrophils increased. Magdalena Ostafin reported that immature neutrophils isolated from AML are characterized by a low ability to secrete ETs, which is in accordance with our findings ( 33 ). It is postulated that the insignificant trend of elevated ETs in ND APL patients is due to the high content of promyelocytes.…”

Neutrophils in cancer carcinogenesis and metastasis

“…The structure of NETs formed by granule proteins and DNA induces the proliferation of cancer cells through high mobility group protein B1 (HMGB1) and NE [ 46 – 48 ]. In hematological malignancies, levels of NETs are found to positively correlated with lymphoma progression or childhood acute leukemia development [ 49 , 50 ].…”

Establishment and validation of a carbohydrate metabolism-related gene signature for prognostic model and immune response in acute myeloid leukemia

“…Inhibition of the key modulation factor of the B cell receptor signaling pathway have been proven to be an effective therapeutic approach for AML ( 63 ). In addition, NET has been implicated in a variety of pathologies from autoimmunity to cancer, and its release was impaired in AML ( 64 ). It may contribute to the increased susceptibility of this population ( 64 ).…”

“…In addition, NET has been implicated in a variety of pathologies from autoimmunity to cancer, and its release was impaired in AML ( 64 ). It may contribute to the increased susceptibility of this population ( 64 ). CAR-T cell therapy has been used for the treatment of AML ( 65 ), which induces T cell activation, proliferation, and effector function through the binding of reprogrammed T cells to relevant antigens on the surface of tumor cells, ultimately leading to tumor cell death ( 66 ).…”