Abstract
Growing evidence highlights the endocannabinoid (EC) system involvement in cancer progression. Lipid mediators of this system are secreted by hematopoietic cells, including the ECs 2-arachidonoyl-glycerol (2AG) and arachidonoyl-ethanolamide (AEA), the 2AG metabolite 1AG, and members of N-acylethanolamine (NAE) family—palmitoyl-ethanolamide (PEA) and oleoyl-ethanolamide (OEA). However, the relevance of the EC system in myeloproliferative neoplasms (MPN) was never investigated. We explored the EC plasma profile in 55 MPN patients, including myelofibrosis (MF; n = 41), polycythemia vera (PV; n = 9), and essential thrombocythemia (ET; n = 5) subclasses and in 10 healthy controls (HC). AEA, PEA, OEA, 2AG, and 1AG plasma levels were measured by LC–MS/MS. Overall considered, MPN patients displayed similar EC and NAE levels compared to HC. Nonetheless, AEA levels in MPN were directly associated with the platelet count. MF patients showed higher levels of the sum of 2AG and 1AG compared to ET and PV patients, higher OEA/AEA ratios compared to HC and ET patients, and higher OEA/PEA ratios compared to HC. Furthermore, the sum of 2AG and 1AG positively correlated with JAK2V617F variant allele frequency and splenomegaly in MF and was elevated in high-risk PV patients compared to in low-risk PV patients. In conclusion, our work revealed specific alterations of ECs and NAE plasma profile in MPN subclasses and potentially relevant associations with disease severity.
Highlights
The endocannabinoid (EC) system is composed by the lipid endogenous compounds— N-arachidonoyl-ethanolamine and 2-arachidonoyl-glycerol (2AG), the enzymatic machinery responsible for ligand synthesis and degradation, and the cannabinoid receptors 1 (CB1) and 2 (CB2) [1]
The cohort included 55 patients affected by myeloproliferative neoplasms (MPN), recruited at the University Hospital of Bologna, and 10 healthy control (HC) volunteers from the general population
MPN patients were subdivided into essential thrombocythemia (ET) (n = 5), polycythemia vera (PV) (n = 9), and MF (n = 41)
Summary
The endocannabinoid (EC) system is composed by the lipid endogenous compounds— N-arachidonoyl-ethanolamine (anandamide, AEA) and 2-arachidonoyl-glycerol (2AG), the enzymatic machinery responsible for ligand synthesis and degradation, and the cannabinoid receptors 1 (CB1) and 2 (CB2) [1]. CB1 and CB2 are G-protein-coupled receptors; CB1 is highly expressed in the central nervous system and in most peripheral tissues, and CB2 is mainly detected in immune cells [4,5] Both receptors are involved in the regulation of cell proliferation, differentiation, apoptosis, and migration. AEA belongs to the N-acyl-ethanolamide (NAE) family, including oleoyl-ethanolamine (OEA) and palmitoyl-ethanolamine (PEA) [3] These signaling lipids share the biosynthetic and degradative machinery as well as non-CB targets, such as the transient receptor potential vanilloid 1 (TRPV1), G-protein-coupled receptors GPR55 and GPR119, and peroxisome proliferator activator receptors (PPAR). For the first time, we investigated the circulating profile defined by levels of the sum of 2AG and 1AG and by the levels and the relative abundances of the NAE AEA, PEA, and OEA in patients affected by MPN, including ET, PV, and MF. We associated the EC and NAE profile with clinical parameters, mutational status, and disease severity to gain further insight into MPN etiology and to highlight potential disease-related biomarkers
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