Methylation variability and LINE-1 activation in multiple myeloma

Multiple myeloma (MM) is a type of hematological cancer that arises from uncontrolled proliferation of plasma cells. In addition to frequent genetic mutations, malignant plasma cells are characterized by alterations to the epigenome. Myeloma cells display a genome-wide loss of DNA methylation and a corresponding increase in active chromatin modifications. The dramatic epigenetic remodeling that occurs in cancer genomes is associated with loss of silencing at transposable elements, which can impact genome regulation. Through paired epigenome and transcriptome profiling of patient derived MM samples, we have found that loss of DNA methylation in MM genomes results in the formation of partially methylated domains that are variable across patients. This loss of DNA methylation coincides with the expression of hundreds of transcripts driven by LINE-1 (L1) retrotransposons that are epigenetically silenced in normal cells. MM samples can be stratified based on L1 activity with distinct gene expression signatures. The high L1 samples are characterized by a more proliferative, less differentiated state as well as inhibition of interferon and genome defense pathways. Several L1 promoters generate chimeric transcripts with adjacent oncogenes. We further find that KRAB-zinc finger proteins (KZFPs) that are responsible for the epigenetic silencing of L1s have abnormally low abundance in MM samples with high L1 activity. These results indicate that cell proliferation in MM is associated with a loss of KZFP expression and activation of L1 elements. SignificanceEpigenome and transcriptional profiling of patient-derived multiple myeloma samples reveals heterogeneous loss of DNA methylation, reduction of KZFP expression and LINE-1 activation as a clinical indicator of progression.