HARBIN, CHINA — Even though the rate of complete remission of acute promyelocytic leukemia (APL) is currently more than 90% because of the use of all-trans retinoic acid (ATRA) with arsenic trioxide (ATO), hemorrhagic mortality has emerged as the most significant barrier to APL-induced remission, according to a new study.
The report in Frontiers in Neurology pointed out that neutrophils extracellular traps (NETs/ETs) cause vascular leakage by damaging the integrity of endothelial cells.1
The lead researchers were from First Affiliated Hospital of Harbin Medical University in China, but the study had participation from the VA Boston Healthcare System, Dana-Farber Cancer Institute, and Harvard Medical School, all in Boston.
The authors noted that they had previously demonstrated that APL cells treated with ATRA/ATO undergo a cell death process, releasing extracellular chromatin; that process is called ETosis/NETosis. “However, the mechanism underlying the involvement of ETs in endothelial injury in APL remain largely unknown,” they added.
The study team sought to anylize the ability of mature and immature neutrophils to release ETs, and their interaction with platelets (PLTs) in APL, adding that discussing the effect of ETs on vascular endothelium in APL was part of their mission.
ETs are involved in antimicrobial defense and in non-infectious diseases, including thrombosis, vasculitis and cancer, according to the report. The authors advised that elevated ETs levels have been detected in plasma and in tissues of many solid tumors, adding, “However, the significance of ETs in hematological tumors, especially APL, has relatively little been established.”
Study results indicated 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.”
On the other hand, 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,” the researchers concluded.
- Wang Y, Wang C, Zuo N, Yang H, Fang S, Shi J. Extracellular Traps Increase Burden of Bleeding by Damaging Endothelial Cell in Acute Promyelocytic Leukaemia. Front Immunol. 2022 Apr 11;13:841445. doi: 10.3389/fimmu.2022.841445. PMID: 35479063; PMCID: PMC9035902.