Neutralize the neutrophils! Neutrophil β1/β2 integrin activation contributes to JAK2-V617F–driven thrombosis

Oh, Stephen T.

doi:10.1172/jci123388

Cited by 3 publications

(5 citation statements)

References 16 publications

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“…The activation and recruitment of leukocytes contributes to the formation of neutrophil extracellular traps (NETs), which are networks made up of genetic material and protein derived from neutrophils, and which favor cell activation, production of reactive oxygen species, platelet activation and aggregation and endothelial damage [ 62 ]. Activated neutrophils express CD11b on the cell surface and secrete elastase and myeloperoxidase, which favors the chemotaxis of neutrophils, monocytes and macrophages and facilitates endothelial adhesion [ 63 , 64 , 65 , 66 ]. Simultaneously, the expression of β1 and β2 integrins in recruited neutrophils is favored, and glycoproteins are expressed by interconnection of the JAK/STAT pathway with Rap1-GT-Pasa, which have affinity for vascular cell adhesion molecules (VCAM-1) and for intercellular adhesion molecules (ICAM-1) expressed by endothelial cells [ 67 , 68 , 69 , 70 ], thus enhancing endothelial adhesion.…”

Section: Implications Of the Jak2 V617f Variant In...mentioning

confidence: 99%

“…Histone-MPO complexes have also been found in the plasma of individuals with MPNs and to be associated with high levels of LDH [ 61 ]. As such, NETosis plays a crucial role in tumor expansion in MPNs by enhancing immunothrombosis and activating hemostasis, thus forming a repetitive cycle [ 66 ].…”

Section: Implications Of the Jak2 V617f Variant In...mentioning

confidence: 99%

“…The expression of these markers induces a hemostatic response through exposure and activation of tissue factor (a product of endothelial damage), directly activating the extrinsic pathway of the coagulation cascade and consequent fibrin production. In this process, activated platelets expose negatively charged phospholipids that confer proteolytic reaction of coagulation factors, acting as mediators between coagulation and inflammation through activation of the complement cascade, especially of C3 and C5 molecules [ 66 ].…”

Section: Implications Of the Jak2 V617f Variant In...mentioning

confidence: 99%

“…Although they are the most frequently used drugs in these diseases, the use of new drugs that inhibit the expression of platelet receptors, platelet adhesion molecules and cytokines would favor the reduction of thrombus formation and, consequently, the development of immunothrombosis [ 5 ]. Likewise, inhibition of the expression of integrins, adhesion molecules and other membrane proteins in neutrophils, monocytes, lymphocytes and endothelial cells constitutes a promising strategy in individuals with BCR/ABL1 negative chronic myeloproliferative neoplasms as treatment targets [ 66 ], especially in those with drug resistance and categorized as high risk.…”

Section: Summary and Perspectivesmentioning

confidence: 99%

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JAK2 Variant Signaling: Genetic, Hematologic and Immune Implication in Chronic Myeloproliferative Neoplasms

et al. 2022

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The JAK2V617F variant constitutes a genetic alteration of higher frequency in BCR/ABL1 negative chronic myeloproliferative neoplasms, which is caused by a substitution of a G ˃ T at position 1849 and results in the substitution of valine with phenylalanine at codon 617 of the polypeptide chain. Clinical, morphological and molecular genetic features define the diagnosis criteria of polycythemia vera, essential thrombocythemia and primary myelofibrosis. Currently, JAK2V617F is associated with clonal hematopoiesis, genomic instability, dysregulations in hemostasis and immune response. JAK2V617F clones induce an inflammatory immune response and lead to a process of immunothrombosis. Recent research has shown great interest in trying to understand the mechanisms associated with JAK2V617F signaling and activation of cellular and molecular responses that progressively contribute to the development of inflammatory and vascular conditions in association with chronic myeloproliferative neoplasms. Thus, the aim of this review is to describe the main genetic, hematological and immunological findings that are linked to JAK2 variant signaling in chronic myeloproliferative neoplasms.

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Section: Implications Of the Jak2 V617f Variant In...mentioning

confidence: 99%

Section: Implications Of the Jak2 V617f Variant In...mentioning

confidence: 99%

Section: Implications Of the Jak2 V617f Variant In...mentioning

confidence: 99%

Section: Summary and Perspectivesmentioning

confidence: 99%

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JAK2 Variant Signaling: Genetic, Hematologic and Immune Implication in Chronic Myeloproliferative Neoplasms

et al. 2022

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“…They are source of proinflammatory cytokines in MPN [24,32,[95][96][97], with an impact on chronic proinflammatory state that contributes to disease pathogenesis. They are involved in tromboinflammation and thrombosis manifestation [98][99][100] as well as in fibrosis [32,101] in MPN. Diverse cytokine receptors expressed on the neutrophil cell surface, that transduce signals through the JAK/STAT pathways and affect their crucial functions [102], represent the most obvious link between neutrophils and MPN pathophysiology.…”

Section: Mpn Neutrophilsmentioning

confidence: 99%

Neutrophil Death in Myeloproliferative Neoplasms: Shedding More Light on Neutrophils as a Pathogenic Link to Chronic Inflammation

Marković

Maslovarić

Djikić

et al. 2022

IJMS

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Neutrophils are an essential component of the innate immune response, but their prolonged activation can lead to chronic inflammation. Consequently, neutrophil homeostasis is tightly regulated through balance between granulopoiesis and clearance of dying cells. The bone marrow is both a site of neutrophil production and the place they return to and die. Myeloproliferative neoplasms (MPN) are clonal hematopoietic disorders characterized by the mutations in three types of molecular markers, with emphasis on Janus kinase 2 gene mutation (JAK2V617F). The MPN bone marrow stem cell niche is a site of chronic inflammation, with commonly increased cells of myeloid lineage, including neutrophils. The MPN neutrophils are characterized by the upregulation of JAK target genes. Additionally, MPN neutrophils display malignant nature, they are in a state of activation, and with deregulated apoptotic machinery. In other words, neutrophils deserve to be placed in the midst of major events in MPN. Our crucial interest in this review is better understanding of how neutrophils die in MPN mirrored by defects in apoptosis and to what possible extent they can contribute to MPN pathophysiology. We tend to expect that reduced neutrophil apoptosis will establish a pathogenic link to chronic inflammation in MPN.

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The role of leukocytes in myeloproliferative neoplasm thromboinflammation

Liu,

Wang,

Huang

et al. 2024

Journal of Leukocyte Biology

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Classic myeloproliferative neoplasms lacking the Philadelphia chromosome are stem cell disorders characterized by the proliferation of myeloid cells in the bone marrow and increased counts of peripheral blood cells. The occurrence of thrombotic events is a common complication in myeloproliferative neoplasms. The heightened levels of cytokines play a substantial role in the morbidity and mortality of these patients, establishing a persistent proinflammatory condition that culminates in thrombosis. The etiology of thrombosis remains intricate and multifaceted, involving blood cells and endothelial dysfunction, the inflammatory state, and the coagulation cascade, leading to hypercoagulability. Leukocytes play a pivotal role in the thromboinflammatory process of myeloproliferative neoplasms by releasing various proinflammatory and prothrombotic factors as well as interacting with other cells, which contributes to the amplification of the clotting cascade and subsequent thrombosis. The correlation between increased leukocyte counts and thrombotic risk has been established. However, there is a need for an accurate biomarker to assess leukocyte activation. Lastly, tailored treatments to address the thrombotic risk in myeloproliferative neoplasms are needed. Therefore, this review aims to summarize the potential mechanisms of leukocyte involvement in myeloproliferative neoplasm thromboinflammation, propose potential biomarkers for leukocyte activation, and discuss promising treatment options for controlling myeloproliferative neoplasm thromboinflammation.

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Neutralize the neutrophils! Neutrophil β1/β2 integrin activation contributes to JAK2-V617F–driven thrombosis

Cited by 3 publications

References 16 publications

JAK2 Variant Signaling: Genetic, Hematologic and Immune Implication in Chronic Myeloproliferative Neoplasms

JAK2 Variant Signaling: Genetic, Hematologic and Immune Implication in Chronic Myeloproliferative Neoplasms

Neutrophil Death in Myeloproliferative Neoplasms: Shedding More Light on Neutrophils as a Pathogenic Link to Chronic Inflammation

The role of leukocytes in myeloproliferative neoplasm thromboinflammation

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