Putative Role of Neutrophil Extracellular Trap Formation in Chronic Myeloproliferative Neoplasms

Abstract

Myeloproliferative neoplasms (MPNs) are hematologic malignancies characterized by gene mutations that promote myeloproliferation and resistance to apoptosis via constitutively active signaling pathways, with Janus kinase 2-signal transducers and the activators of transcription (JAK-STAT) axis as a core part. Chronic inflammation has been described as a pivot for the development and advancement of MPNs from early stage cancer to pronounced bone marrow fibrosis, but there are still unresolved questions regarding this issue. The MPN neutrophils are characterized by upregulation of JAK target genes, they are in a state of activation and with deregulated apoptotic machinery. Deregulated neutrophil apoptotic cell death supports inflammation and steers them towards secondary necrosis or neutrophil extracellular trap (NET) formation, a trigger of inflammation both ways. NETs in proinflammatory bone marrow microenvironment induce hematopoietic precursor proliferation, which has an impact on hematopoietic disorders. In MPNs, neutrophils are primed for NET formation, and even though it seems obvious for NETs to intervene in the disease progression by supporting inflammation, no reliable data are available. We discuss in this review the potential pathophysiological relevance of NET formation in MPNs, with the intention of contributing to a better understanding of how neutrophils and neutrophil clonality can orchestrate the evolution of a pathological microenvironment in MPNs.

Assessment of Total Antioxidant Capacity, 8-Hydroxy-2′-deoxy-guanosine, the Genetic Landscape, and Their Associations in BCR::ABL-1-Negative Chronic and Blast Phase Myeloproliferative Neoplasms

“…In addition, other types of measurements, e.g., ROS quantification, require the immediate evaluation of fresh samples due to the quick degradation of ROS, and thus, this type of assessment could not be conducted using frozen plasma. However, we plan to address these limitations in future prospective studies, in which we will collect more blood components and other types of samples (e.g., urine) from MPN and sAML patients to analyze more markers of oxidative and nitrosative stress, inflammation levels, antioxidant enzymes, neutrophil extracellular traps, and other biomarkers [ 33 , 34 ]. In addition, as extensive genetic testing was only available in a limited number of cases, particularly in sAML patients, several observations need to be interpreted with caution and require validation in future assessments.…”

Common molecular signatures between coronavirus infection and Alzheimer’s disease reveal targets for drug development

“…On the other hand, commonly up-regulated genes enriched in pathways involved in inflammatory responses and cell death, such as Neutrophil extracellular traps (NETs), that are structures that are formed as a defense mechanism by neutrophils to trap and neutralize invading pathogens. However, these structures can also contribute to the development of various pathophysiological conditions, including sterile inflammation and autoimmunity [40]. (Figure 5, Supplementary file 1).…”

Philadelphia chromosome-negative myeloproliferative chronic neoplasms: is clonal hematopoiesis the main determinant of autoimmune and cardio-vascular manifestations?

“…JAK , through its activated pathways and regulatory molecules, such as STAT, AKT, and Raf-MEK-ERK, may regulate the NET formation both in normal neutrophils and neutrophils in pathological situations. In addition, in JAK2-mutated PV patients, peptidyl arginine deiminase (PAD4), HIF-mediated gene expression, and RAP1 were increased, leading to the production of NET ( 72 – 74 ). Moreover, RAP1 activates integrin signaling and enhances the adhesion of clonal neutrophils in PV.…”