Hypermethylierung-assoziierte Dysregulation der WNT-Antagonisten SFRP 1, 2, 4 und 5 beim Multiplen Myelom

Abstract

There is increasing evidence that epigenetic changes, especially DNA methylation affecting promoter-associated CpG islands, play an important role in the pathogenesis of hematopoietic malignancies. In this study, we detected simultaneous hypermethylation of multiple WNT inhibitors in both MM cell lines and primary samples from patients with MM and MGUS. Our data are in accordance with a recent study by Chim et al. and confirm that concurrent promoter hypermethylation of SFRP genes is a common epigenetic event in MM. We found that aberrant methylation of at least one gene occurred in 48/76 (63.2%) samples. SFRP 1 and SFRP 2 were the most frequently affected genes. Hypermethylation of SFRP genes could be observed in all MM stages and also in 2/3 cases with MGUS indicating that epigenetic dysregulation of WNT antagonists may be an early event in the pathogenesis of malignant plasma cell disorders. In contrast, SFRP 5 hypermethylation was only detected in stage III MM or in PCL, and the association between hypermethylation of SFRP 5 and PCL was statistically significant (p=0.0046). There were no correlations between the methylation status of any SFRP gene with the clinical parameters age and gender, white blood cell count, haemoglobin, platelet count, creatinine or calcium. Epigenetic silencing of the SFRP genes may contribute to dysregulation of the WNT pathway in plasma cells. Further studies are warranted to elucidate the functional consequences of aberrant WNT signaling by downregulation of the SFRP genes in the pathogenesis of MM. Additionally, the increasing evidence for the important role of DNA methylation changes in malignant plasma cell disorders may serve as a basis for the use of epigenetically targeted therapeutic approaches in MM in the future. This study and the results of the group of Roman-Gomez et al. indicate the function of the SFRPs is not redundant in hematologic malignancies, in contrast to the findings in solid tumors. Further studies are needed to eluciate the diffenrence role of the SFRPs