Epigenetic Silencing of WNT Inhibitory Proteins; SFRP1 and DKK3 in Acute Leukemia

Abstract

Background: Over-activation of Wnt (derived from names of two genes; DrosophilaWingless and mouse Int-1) pathway is incriminated in leukemogenesis. Functionalloss of Wnt antagonists; DKK (Dikkopf) and SFRPs (secreted frizzled-relatedprotein), can contribute to Wnt hyper-activation. Silencing of Wnt antagonists byhypermethylation is reported in human malignancies as well as in hematopoieticmalignancies. Our aim was to estimate the frequency and the possible impact ofhypermethylation of the SFRP1 and DKK3 in acute leukemia. Methods: We evaluatedSFRP1 and DKK3 methylation status using methylation specific polymerase chainreaction (MS-PCR) in 50 acute myeloid leukemia (AML) and 30 B-acutelymphoblastic leukemia (B-ALL) patients and 20 age and sex matched controls.Results: The frequency of methylation in B-ALL patients was 40% for SFRP1, 40%for DKK-3, in AML patients; the frequency was 44% for SFRP1, 36% for DKK-3. Allthe control subjects had no aberrant methylation in either SFRP1 or DKK-3. B-ALLand AML groups showed no statistical significant difference in the frequency ofSFRP1 or DKK-3 methylation. B-ALL patients with M-SFRP1 had a significantlyhigher mean platelets count and a lower mean age compared to B-ALL patients withUM-SFRP1, no other significant clinical or hematological difference wasencountered between patients with M-SFRP1 and UM-SFRP1 or between M-DKK3and UM-DKK3 patients in the ALL or the AML group. Different B-ALL and AMLprognostic cytogenetic groups showed nearby frequency of SFRP1 and DKK3methylation. Conclusion: SFRP1 and DKK3 methylation is frequent in acuteleukemia. Treatment with demethylating agents may reverse the overactivated Wntsignaling in patients with methylated phenotype.