Accumulation of lncRNAs in cytoplasm upon DIS3 depletion leads to production of cryptic peptides detected in Multiple Myeloma.

Some long noncoding (lnc)RNAs harbor the potential to produce functional micropeptides. Despite the increasing recognition of their significance, the regulatory dynamics of cytoplasmic lncRNA expression, decay, and translation remain poorly understood. Here, we investigate the role of ribonucleases in controlling cytoplasmic levels of lncRNAs. By transcriptomic analysis we identified DIS3 but not XRN1 as a major enzyme preventing accumulation of lncRNAs in cytoplasm. Single-molecule experiments illustrate an example of DIS3-sensitive transcript (DIST) accumulation in the nucleus preceding the one in the cytoplasm, suggesting a sequential series of events. Approximately 14.5% of the DISTs contain at least one actively translated open reading frame (ORF). This finding is highly relevant to Multiple Myeloma bone marrow cancer patients’ cases with mutations impairing the DIS3 enzymatic activity and revealing a subgroup of overexpressed translatable DISTs. Immunopeptidomic approach identified the association of DIST-derived peptides with the major histocompatibility complex class I (MHCI). Notably, the low expression of DISTs in healthy tissues emphasizes their potential as targets for cancer-specific immunotherapies. Our findings shed light on the intricate regulatory mechanisms governing cytoplasmic lncRNA dynamics and highlight their clinical relevance in the context of bone marrow cancers, providing a foundation for future investigations into novel therapeutic strategies.