Epigenetic dysregulation of secreted frizzled-related proteins in myeloproliferative neoplasms complements the JAK2V617F-mutation

Aberrant methylation among primary MPN samples was 4% for SFRP-1, 25% for SFRP-2, 2% for SFRP-4, and 0% for SFRP-5. Hypermethylation of SFRP-2, which was the most frequently hypermethylated gene in our study, could not be correlated to any specific MPN subtype. However, we detected a significant correlation between SFRP-2 methylation and presence of a JAK2V617F mutation (P = 0.008). None of the 10 CML samples showed any SFRP-methylation.Our data indicate that epigenetic dysregulation of the Wnt signaling pathway is a common event in MPN with aberrant methylation of at least one SFRP being detected in 25% of the primary patient samples and in 30% if only accounting for Ph-MPN. A significant correlation between SFRP-2 methylation and presence of JAK2V617F in our data supports the hypothesis that epigenetic dysregulation may be a complementary mechanism to genetic aberrations. Aberrant methylation of crucial stem cell maintenance genes seems to contribute to disease pathogenesis in Ph-MPN.Classical myeloproliferative neoplasms (MPN) according to the WHO classification constitute a group of hematopoietic malignancies and comprise chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). MPN share a common trait of unregulated trilineage myeloproliferation and monoclonal hematopoiesis originating from genetically transformed hematopoietic stem cells. CML is characterized by the well-known, disease-causing translocation t(9;22) with the corresponding fusion gene BCR-ABL1. In contrast, BCR-ABL1-negative MPN (Ph-MPN) present heterogenously in terms of clinical characteristics and cytogenetic aberrations. More than 80% of chromosomal aberrations are imbalanced changes, with trisomies of chromosomes 8 and 9 being the most frequent aberrations. Further cytogenetic findings are chromosomal deletions of 5q, 11q, 13q, 20q, 12p, and Y [1].The discovery of the Janus kinase 2 (JAK2) V617F mutation in 2005 has modified th