Endothelial damage and a thin intercellular fibrin network promote haemorrhage in acute promyelocytic leukaemia

Wang, Chunxu; Yu, Mengxue; Zhou, Peng; Li, Baorong; Liu, Yingmiao; Wang, Lixiu; Chen, Xiaojing; Du, Jingwen; Wang, Yufeng; Zhang, Jinming; Jing, Haijiao; Feng, Yiming; Zhang, Yue; Li, Yueyue; Dong, Zengxiang; Fang, Shaohong; Novakovic, Valerie A.; Zhou, Jin; Shi, Jialan

doi:10.1016/j.ebiom.2020.102992

Cited by 10 publications

(12 citation statements)

References 55 publications

(64 reference statements)

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“…Each of the donors signed an informed consent form. APL was diagnosed based on clinical data, morphology, cytochemistry, immunology, cytogenetics and molecular pathology testing, or confirmation of the presence of the t ( 15 , 17 ) (PML-RARα) fusion gene ( 26 ). Table 1 summarizes main clinical characteristics of patients.…”

Section: Methodsmentioning

confidence: 99%

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

Wang

Zuo

et al. 2022

Front. Immunol.

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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.

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Section: Methodsmentioning

confidence: 99%

“…We previously showed that pathological neutrophils, APL cells or NB4 cells, cause bleeding by damaging endothelium in APL ( 17 ). However, the role of ETs, a product of neutrophils, in endothelial injury- related hemorrhage is unclear in APL.…”

Section: Introductionmentioning

confidence: 99%

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

Wang

Zuo

et al. 2022

Front. Immunol.

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“…The depletion of neutrophils has been shown to reverse experimental thrombosis ( 9 , 10 ). Another study reported that neutrophils produce tissue factor (TF) and contribute to the formation of thrombosis in vivo and in vitro ( 11 ).…”

Section: Introductionmentioning

confidence: 99%

The Emerging Role of Neutrophil Extracellular Traps in Arterial, Venous and Cancer-Associated Thrombosis

Zhou

Tao

Shen

et al. 2021

Front. Cardiovasc. Med.

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Neutrophils play a vital role in the formation of arterial, venous and cancer-related thrombosis. Recent studies have shown that in a process known as NETosis, neutrophils release proteins and enzymes complexed to DNA fibers, collectively called neutrophil extracellular traps (NETs). Although NETs were originally described as a way for the host to capture and kill bacteria, current knowledge indicates that NETs also play an important role in thrombosis. According to recent studies, the destruction of vascular microenvironmental homeostasis and excessive NET formation lead to pathological thrombosis. In vitro experiments have found that NETs provide skeletal support for platelets, red blood cells and procoagulant molecules to promote thrombosis. The protein components contained in NETs activate the endogenous coagulation pathway to promote thrombosis. Therefore, NETs play an important role in the formation of arterial thrombosis, venous thrombosis and cancer-related thrombosis. This review will systematically summarize and explain the study of NETs in thrombosis in animal models and in vivo experiments to provide new targets for thrombosis prevention and treatment.

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“…In this study, we verified that NET deposition is more abundant in cancer tissues of patients with GC, accompanied by significant NET infiltration around miANGPT2cro vessels. Related studies have also confirmed that NETs can damage endothelial cells and recruit platelets to the injured site, leading to the formation of deep venous thrombosis ( 36 , 37 ). This evidence shows that NETs can affect endothelial cells and trigger the onset and development of GC in the TME.…”

Section: Discussionmentioning

confidence: 87%

Immunoregulation and clinical significance of neutrophils/NETs-ANGPT2 in tumor microenvironment of gastric cancer

Yang

Zou

et al. 2022

Front. Immunol.

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Although significant progress has been made in the study of gastric cancer (GC), clinicians lack reliable protein markers for accurate diagnosis and tumor stratification. Neutrophil extracellular traps (NETs) are networks of extracellular fibers composed of DNA from neutrophils. We have previously reported that abundant NETs are deposited in GC, damaging human umbilical vein endothelial cells (HUVECs) and triggering the release of tissue factors, leading to a hypercoagulable state in GC. However, the specific effects of NETs on HUVECs are unclear. We aimed to explore the functional changes caused by NETs on HUVECs, providing evidence that NETs may fuel GC progression. Through quantitative proteomics, we identified 6182 differentially expressed proteins in NET-stimulated HUVECs by TMT. The reliability of the TMT technique was confirmed by parallel reaction monitoring (PRM) analysis of 17 differentially expressed proteins. Through bioinformatics analysis, we found that NETs upregulate ANGPT2 in HUVECs. We comprehensively analyzed the prognosis, biological function, immune response, and therapeutic value of ANGPT2 in GC. We found that overexpression of ANGPT2 in GC is associated with poor prognosis and potentially regulates multiple biological functions. At the same time, ANGPT2 also predicted immunotherapeutic and chemotherapeutic responses in GC. In conclusion, NETs promoted ANGPT2 overexpression in the GC microenvironment. In the future, the neutrophil/NETs-ANGPT2 axis may provide a new target for the treatment of GC.

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Endothelial damage and a thin intercellular fibrin network promote haemorrhage in acute promyelocytic leukaemia

Cited by 10 publications

References 55 publications

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

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

The Emerging Role of Neutrophil Extracellular Traps in Arterial, Venous and Cancer-Associated Thrombosis

Immunoregulation and clinical significance of neutrophils/NETs-ANGPT2 in tumor microenvironment of gastric cancer

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