Methylation variability and LINE-1 activation in multiple myeloma

Area of Science:

• Hematological Oncology
• Epigenetics
• Cancer Genomics

Background:

• Multiple myeloma (MM) is a plasma cell cancer characterized by genetic mutations and epigenetic alterations.
• Malignant plasma cells exhibit genome-wide DNA hypomethylation and increased active chromatin marks.
• Epigenetic remodeling in cancer can lead to the reactivation of silenced transposable elements, impacting genome regulation.

Purpose of the Study:

• To investigate the role of DNA methylation loss and transposable element activation in multiple myeloma.
• To characterize the relationship between epigenetic changes, gene expression, and cellular states in MM.
• To identify potential therapeutic targets related to epigenetic dysregulation in MM.

Main Methods:

• Paired epigenome and transcriptome profiling of patient-derived MM samples.
• Analysis of DNA methylation patterns, including partially methylated domains.
• Quantification of LINE-1 (L1) retrotransposon activity and associated gene expression.
• Assessment of KRAB-zinc finger protein (KZFP) abundance.

Main Results:

• Loss of DNA methylation in MM creates patient-variable partially methylated domains.
• This hypomethylation correlates with the expression of hundreds of LINE-1 (L1) retrotransposon-driven transcripts.
• MM samples stratified by L1 activity show distinct gene expression signatures, with high L1 activity linked to proliferation and suppressed immune pathways.
• Abnormally low abundance of KRAB-zinc finger proteins (KZFPS) was observed in MM samples with high L1 activity.

Conclusions:

• Cell proliferation in multiple myeloma is associated with a loss of KZFP expression and subsequent activation of L1 elements.
• L1 activation may contribute to the malignant phenotype in MM through various mechanisms, including oncogene transcription.
• Epigenetic dysregulation, particularly L1 reactivation, represents a potential avenue for MM research and therapy.