Increased Dkk‐1 plasma levels may discriminate disease subtypes in myeloproliferative neoplasms

Abstract

Alterations in the bone marrow niche induced by abnormal production of cytokines and other soluble factors have been associated with disease progression in classical BCR‐ABL1 negative myeloproliferative neoplasms (MPN). Variations in circulating proteins might reflect local disease processes and plasma proteome profiling could serve to identify possible diagnostic and prognostic biomarkers. We employed a human cytokine array to screen for 105 distinct analytes in pooled plasma samples obtained from untreated young MPN patients (<35 years) with different clinical phenotypes and driver mutations, as well as from healthy individuals. Among molecules that exhibited significantly increased levels in MPN patients versus controls, the top of the list was represented by Dickkopf‐related protein 1 (Dkk‐1), which also showed the highest potential for discrimination between MPN subtypes. In the next step, a quantitative ELISA was used to measure plasma Dkk‐1 levels in 30 young‐onset MPN—10 essential thrombocythemia (ET), 10 polycythemia vera (PV), 10 pre‐fibrotic primary myelofibrosis (pre‐PMF)—and 10 controls. The results suggested that plasma Dkk‐1 levels could differentiate ET from pre‐PMF, in JAK2 V617F‐positive as well as in CALR‐positive patients, and also ET from PV in JAK2 V617F‐positive patients.

Comparison of Proteome Composition of Serum Enriched in Extracellular Vesicles Isolated from Polycythemia Vera Patients and Healthy Controls

“…Polycythemia vera, one of the Philadelphia chromosome negative myeloproliferative neoplasms, is characterized by increased bone marrow hematopoiesis, resulting in the overproduction of erythrocytes, and frequently also of platelets and leukocytes. A typical complication of this disorder is thrombosis, which is a result of the hypercoagulable state associated with excessive amounts of blood cells and inflammatory response [20,21,22]. PV is associated with persistent enhanced platelet activation.…”

“…On the other hand, somatic mutations in the endoplasmic reticulum chaperone gene (CALR) are detectable in a majority of myeloproliferative neoplasms (MPN) patients with non-mutated JAK2 and in a small proportion of MPN somatic mutations in the MPL gene have been also reported [18,19]. There are two mechanisms of a hypercoagulable state associated with PV–firstly, involving the abnormal components of the hematopoietic system (platelets, erythrocytes and leucocytes) which are derived from the clonal proliferation of the hematopoietic progenitor cells and prothrombotic phenotype; secondly, inflammatory response from the host towards cytokines and the inflammatory mediators released by malignant cells [20,21,22]. Although it is known that extracellular vesicles released from cell membranes and circulating in the blood can directly contribute to thrombosis through their procoagulant activity, the potential association between the proteomic composition of EVs and the risk of thrombotic events in PV has not been described before.…”

Cytokine Profiling in Myeloproliferative Neoplasms: Overview on Phenotype Correlation, Outcome Prediction, and Role of Genetic Variants

“…In the same year, the human cytokine array method was utilized by Mambet et al to investigate plasma cytokine levels in a cohort of young (<35 years) MPN patients (N = 10 PV, N = 10 ET, and N = 10 prePMF): angiopoietin-1, Dickkopf-related protein (Dkk)-1, Epidermal Growth Factor (EGF), IP-9, and PDGF were found elevated as compared to controls, with Dkk-1 levels showing the highest potential for discrimination between MPN subtypes (prePMF > PV > ET) [73].…”

Inflammation-Related Patterns in the Clinical Staging and Severity Assessment of Chronic Kidney Disease

“…The discovery of Wnt inhibitors, among them Dickkopf-related protein 1 (Dkk-1), released during renal repair as crucial components of mineral bone disorder (MBD) pathogenesis, suggests that additional pathogenic factors need to be explored [6, 7].…”