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

• Main Authors: Bennemann Karla, Galm Oliver, Wilop Stefan, Schubert Claudia, Brümmendorf Tim H, Jost Edgar
• Format: Article
• Language: English
• Published: BMC 2012-08-01
• Series: Clinical Epigenetics
• Subjects: DNA hypermethylation; MPN; SFRP; Tumor suppressor gene; JAK2
• Online Access: http://www.clinicalepigeneticsjournal.com/content/4/1/12
• ISSN: 1868-7083

<p>Abstract</p> <p>Background</p> <p>Secreted frizzled-related proteins (<it>SFRPs</it>) are antagonists of the Wnt signaling pathway, which plays a central role in stem cell maintenance and differentiation of stem cells and hematopoietic progenitors. Epigenetic downregulation of <it>SFRPs</it> by promoter hypermethylation has been described to be involved in the pathogenesis of hematopoietic malignancies. There is an association between aberrant Wnt signaling and the established cancer stem cell concept. In contrast to <it>BCR-ABL1</it>-positive chronic myeloid leukemia CML, <it>BCR-ABL1</it>-negative myeloproliferative neoplasms (Ph^-MPN) are characterized by the frequent occurrence of an autoactivating mutation in the <it>JAK2</it> tyrosine kinase (<it>JAK2V617F</it>) or other mutations in the JAK-STAT pathway. However, pathogenetic mechanisms of <it>JAK2</it> mutated or unmutated Ph^-MPN remain not completely understood. We determined the promoter methylation status of <it>SFRP-1, -2, -4</it>, and -<it>5</it> in 57 MPN patient samples by methylation-specific polymerase chain reaction (PCR) (MSP). <it>JAK2V617F</it> was assessed by allele-specific PCR.</p> <p>Results</p> <p>Aberrant methylation among primary MPN samples was 4% for <it>SFRP-1</it>, 25% for <it>SFRP-2</it>, 2% for <it>SFRP-4</it>, and 0% for <it>SFRP-5</it>. Hypermethylation of <it>SFRP-2</it>, 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 <it>SFRP-2</it> methylation and presence of a <it>JAK2V617F</it> mutation (<it>P</it> = 0.008). None of the 10 CML samples showed any <it>SFRP</it>-methylation.</p> <p>Conclusions</p> <p>Our data indicate that epigenetic dysregulation of the Wnt signaling pathway is a common event in MPN with aberrant methylation of at least one <it>SFRP</it> being detected in 25% of the primary patient samples and in 30% if only accounting for Ph^-MPN. A significant correlation between <it>SFRP-2</it> methylation and presence of <it>JAK2V617F</it> 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.</p>