Objectives
Multiple myeloma (MM) is plasma cell malignancy that remains incurable due to the development of drug resistance (DR). Next to genetic defects, epigenetic aberrations also contribute to MM pathogenesis. To counter DR, we aim to further explore the exact role of epigenetic modifiers (epiplayers) in MM cell biology and DR. Using the publicly available RNA-seq data form matched newly diagnosed and relapsed samples from the MMRF CoMMpass study, we recently found that the epiplayer DNA methyltransferase 3B (DNMT3B) is significantly upregulated in relapsed samples. This suggests a role for DNMT3B in DR in MM. Here, we examined the expression, prognostic value and role of DNMT3B in MM.
Methods
To evaluate the basal expression and prognostic value of DNMT3B mRNA in terms of overall survival the publicly available gene expression profiling datasets GSE4581 and GSE9782 were used. To examine the effect of the DNMT3B specific inhibitor Nanaomycin A on cell viability and apoptosis, a CellTiter-Glo viability assay and AnnexinV/7AAD stainings were used respectively.
Results
Using publicly available gene expression profiling data, we found that high DNMT3B mRNA levels correlate with a worse disease outcome in both newly diagnosed and relapsed MM patients. Moreover, DNMT3B mRNA levels were found significantly increased in human MM cell lines (HMCLs) compared to primary MM cells. Nanaomycin A treatment of HMCLs with high DNMT3B levels strongly reduced MM cell viability and induced apoptosis. In contrast, BMSC viability was only slightly affected by Nanaomycin A, indicating that Nanaomycin A is not as toxic for the BMSC as for the MM cells.
Conclusion
Together, our findings indicate that DNMT3B could indeed play an important role in MM cell survival. In the future, the role of DNMT3B in MM cell biology and DR and the therapeutic potential of DNMT3B-targeting will be further evaluated.

The role of the de novo DNA methyltransferase DNMT3B in multiple myeloma cell survival and drug resistance