CD18 promoter methylation is associated with a higher risk of thrombotic complications in primary myelofibrosis

Abstract

Morbidity and mortality of BCR-ABL1-negative myeloproliferative neoplasm (MPN) patients are influenced by disease-related hemostatic complications, mostly of thrombotic nature. The pathogenesis of thrombosis is multifactorial: in particular, it has been demonstrated that a deregulated expression of Mac1 (also known as surface receptor integrin CD18/CD11b) by leukocytes has a role in favoring platelets’ activation in MPN patients. Based on these data, we investigated the epigenetic status of CD18/CD11b in 78 primary myelofibrosis (PMF) patients to explore any possible association between the epigenetic profiles of these two genes and thrombotic risk. The percentage of CD18 methylation in the PMF samples ranged from hypomethylated to hypermethylated (range: 11–90 %, mean: 64 %), whereas in controls CD18 methylation status clustered in a more restricted interval (range: 24–68 %, mean: 45 %; cases vs. controls: p = 0.006). Furthermore, the results showed that CD18 hypermethylation (>76 % methylation) was correlated with thrombotic complications. On the contrary, CD11b promoter resulted unmethylated (1–5 %) in both cases and controls. Previous studies showed that older age, JAK2V617F mutation, and thrombophilia might play a role in MPN patients’ thrombotic risk. In our cases, the prognostic value of these variables was coherent, being thrombotic events significantly associated with age >65 years (p = 0.001), JAK2 mutation (p = 0.01), and positive thrombophilia tests (p = 0.04). However, multivariate analysis showed that only CD18 methylation and age >65 years were independent prognostic factors of thrombosis (p = 0.02 and p = 0.04, respectively). Taken together, our findings suggest a possible role of CD18 epigenetic regulation in the pathogenesis of the thrombotic complications in PMF patients.