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

Abstract

The rate of complete remission of acute promyelocytic leukemia (APL) is currently over 90% because of the use of all-trans retinoic acid (ATRA) with arsenic trioxide (ATO). However, hemorrhagic mortality has emerged as the most significant barrier to APL-induced remission. Neutrophils extracellular traps (NETs/ETs) cause vascular leakage by damaging the integrity of endothelial cells. We have previously demonstrated that APL cells treated with ATRA/ATO undergo a cell death process, releasing extracellular chromatin, termed ETosis/NETosis. However, the mechanism underlying the involvement of ETs in endothelial injury in APL remain largely unknown. Here, we analysed the ability of mature and immature neutrophils to release ETs, and their interaction with platelets (PLTs) in APL. Importantly, the effect of ETs on vascular endothelium in APL was discussed. Our results showed that the ability of immature neutrophils to release ETs was impaired in APL, whereas mature neutrophils produced ETs, which were associated with activated PLTs. Moreover, ATRA+ATO induced immature neutrophil differentiation, as well as increased the release of ETs from mature neutrophils. The excessive ETs damaged endothelial cells, causing blood cell leakage. Removing ETs using DNase 1 alleviated endothelial damage and improved blood cells leakage. Our results indicate that vascular endothelial injury is at least partially associated with ETs in APL, and that targeting ETs production may be an effective approach for relieving vascular leakage and reducing the burden of bleeding in APL.

Integrated bioinformatics analysis and network pharmacology to explore the potential mechanism of Patrinia heterophylla Bunge against acute promyelocytic leukemia

“…Targeting extracellular traps production may be an effective strategy to alleviate vascular leakage and reduce the incidence of bleeding in APL. [ 58 ] Chemokines are chemotactic cytokines that regulate cell migration, positioning and interaction. The chemokine axes are crucial in the leukemia microenvironment and are also involved in the migration and extravasation of leukemic cells.…”

NETs-Induced Thrombosis Impacts on Cardiovascular and Chronic Kidney Disease

“…78 NETs also impact the endothelium and thereby on the thrombotic risk through induction of endothelial cell activation and induction of tissue factor, 79 as well as inducing endothelial cell damage or vascular leakage. 80,81 Hence NET interference could also reduce thrombotic risk through less endothelial cell activation and reduction of vascular leakage.…”

Neutrophil extracellular traps in tumor progression and immunotherapy

“…Accumulating evidence suggests that the TME can induce NET formation in various types of cancer, including hematologic malignancy ( 72 – 74 ) and solid tumors, such as breast cancer ( 75 ), ovarian cancer ( 76 ), gastric cancer ( 77 ), hepatic carcinoma ( 78 ), lung cancer ( 79 ), and colon cancer ( 80 , 81 ). In particular, studies have revealed that NETs are increased in the peripheral blood and tumor tissues of patients with cancer ( 16 , 76 , 82 ).…”