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

Bennemann Karla, Galm Oliver, Wilop Stefan, Schubert Claudia, Brümmendorf, Jost, Jost Edgar

Description

Secreted frizzled-related proteins ( SFRPs ) 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 SFRPs 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 BCR-ABL1 -positive chronic myeloid leukemia CML, BCR-ABL1 -negative myeloproliferative neoplasms (Ph - MPN) are characterized by the frequent occurrence of an autoactivating mutation in the JAK2 tyrosine kinase ( JAK2V617F ) or other mutations in the JAK-STAT pathway. However, pathogenetic mechanisms of JAK2 mutated or unmutated Ph - MPN remain not completely understood. We determined the promoter methylation status of SFRP-1, -2, -4 , and - 5 in 57 MPN patient samples by methylation-specific polymerase chain reaction (PCR) (MSP). JAK2V617F was assessed by allele-specific PCR. Results 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. Conclusions 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.

Sujets

• MPN
• Tumor suppressor gene

Informations

• Publié par: biomed
• Publié le: 01 janvier 2012
• Nombre de lectures: 9
• Langue: English

Extrait

Bennemannet al. Clinical Epigenetics2012,4:12 http://www.clinicalepigeneticsjournal.com/content/4/1/12

R E S E A R C H

Open Access

Epigenetic dysregulation of secreted frizzledrelated proteins in myeloproliferative neoplasms complements the JAK2V617Fmutation * Karla Bennemann, Oliver Galm, Stefan Wilop, Claudia Schubert, Tim H Brümmendorf and Edgar Jost

Abstract Background:Secreted frizzledrelated proteins (SFRPs) 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 ofSFRPsby 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 toBCRABL1positive chronic myeloid leukemia CML,BCRABL1negative  myeloproliferative neoplasms (Ph MPN) are characterized by the frequent occurrence of an autoactivating mutation in theJAK2tyrosine kinase (JAK2V617F) or other mutations in the JAKSTAT pathway. However, pathogenetic  mechanisms ofJAK2mutated or unmutated Ph MPN remain not completely understood. We determined the promoter methylation status ofSFRP1, 2, 4, and 5in 57 MPN patient samples by methylationspecific polymerase chain reaction (PCR) (MSP).JAK2V617Fwas assessed by allelespecific PCR. Results:Aberrant methylation among primary MPN samples was 4% forSFRP1, 25% forSFRP2, 2% forSFRP4, and 0% forSFRP5. Hypermethylation ofSFRP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2methylation and presence of aJAK2V617Fmutation (P= 0.008). None of the 10 CML samples showed any SFRPmethylation. Conclusions:Our data indicate that epigenetic dysregulation of the Wnt signaling pathway is a common event in MPN with aberrant methylation of at least oneSFRPbeing detected in 25% of the primary patient samples and in  30% if only accounting for Ph MPN. A significant correlation betweenSFRP2methylation and presence of JAK2V617Fin 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. Keywords:DNA hypermethylation, MPN, SFRP, Tumor suppressor gene, JAK2

* Correspondence: [e-mail] Clinic for oncology, hematology and stem cell transplantation, Universitätsklinikum Aachen, RWTH Aachen, Pauwelsstraße 30, Aachen 52074, Germany

© 2012 Bennemann et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.