Abstract B006: Methylation variability and LINE-1 activation in plasmablastic multiple myleoma

Abstract Background: Plasmablastic multiple myeloma (PMM), a subtype of multiple myeloma (MM), is characterized by immature plasma cells in the bone marrow. PMM is considered a high-risk disease due to its aggressive nature and reduced survival rates. The dramatic epigenetic remodeling that occurs in cancer genomes is associated with loss of silencing at transposable elements. Several consequences of this loss of silencing at TEs have been documented, from TEs being co-opted by the cancer genome for gene regulation, a process known as ‘onco-exaptation’, to genome instability mediated by transposition of LINE-1 (L1) elements. Among the mechanisms involved in the epigenetic repression of TEs are Krüppel-associated box (KRAB) domain zinc finger proteins (KZFPs) that target TEs through sequence specific binding and recruit repressor complexes to epigenetically suppress repeat elements. Methods: Formalin-fixed paraffin-embedded samples from PMM patients were characterized using stranded RNA sequencing for transcriptome profiling and whole-genome bisulfite sequencing for methylome analysis. Publicly available RNA-seq data from normal bone marrow plasma cells (BMPCs) and MM patients were obtained from published studies and the Multiple Myeloma Research Foundation (MMRF). Pipelines for TE transcript detection and methylation status were optimized to ensure accurate alignment within highly repetitive regions. Results: Loss of DNA methylation in PMM samples, as compared to normal BMPCs, results in the formation of partially methylated domains that are variable across patient samples. This loss of DNA methylation coincides with the expression of several hundred transcripts driven by LINE-1 (L1) retrotransposons that are epigenetically silenced in normal cells. Evolutionarily young L1 subfamilies, such as L1PA2 and L1PA3, preferentially lose methylation and are transcribed. While DNA methylation at CpG islands overlapping L1 elements is reduced in PMM samples compared to resting B cells, DNA methylation entropy is increased at these CpG islands within L1 elements in PMM samples. Transcript levels of specific KZFPs, including KZFPs that target L1PA2 and L1PA3 elements, are inversely correlated with the activity of L1 subfamilies. A similar degree of L1 activation is present in myeloma samples from the MMRF, where L1 activity correlates with poor survival outcomes. Samples with elevated L1 activity have a distinct gene expression signature related to a more proliferative, less differentiated state and inhibition of p53 and interferon pathways. Conclusion: The heterogeneous loss of DNA methylation at LINE1 regions in PMM samples contributes to heterogenous transposon activity with the potential to alter genome regulation. Patients with high L1 activity display unique gene expression signatures, potentially mediating the tolerance of high TE activity. Targeting LINE1 regulation may represent a novel strategy to slow PMM progression. Further studies are needed to assess how LINE1 activation affects genome regulation. Citation Format: Qianhui Wan, Amy Leung, Mahek Vinod Bhandari, Hiroyuki Kato, Joo Song, Dustin Schones. Methylation variability and LINE-1 activation in plasmablastic multiple myleoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Methylation, Clonal Hematopoiesis, and Cancer; 2025 Feb 1-4; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2025;85(3 Suppl):Abstract nr B006.