SORT1/LAMP2-mediated extracellular vesicle secretion and cell adhesion are linked to lenalidomide resistance in multiple myeloma

Multiple myeloma (MM) is a hematopoietic malignancy whose prognosis has improved with the development of new agents such as lenalidomide over the last decade. However, long-term exposure to drugs induces the acquisition of resistance by MM cells and leads to treatment failure and poor prognosis. Here, we show the molecular and cellular mechanisms of lenalidomide resistance in MM. In a comparison between lenalidomide-resistant cell lines and the parental cell lines, extracellular vesicle (EV) secretion and adherence abilities were significantly elevated in the resistant cells. Whole-transcriptome analysis revealed that the SORT1 and LAMP2 genes were key regulators of EV secretion. Silencing of these genes caused decreased EV secretion and loss of cell adhesion in the resistant cells, resulting in increased sensitivity to lenalidomide. Analysis of publicly available transcriptome data confirmed the relationship between genes related to EV secretion and cell adhesion and patient prognosis. Together, our findings reveal a novel mechanism of lenalidomide resistance in MM mediated by EV secretion and cell adhesion via SORT1 and LAMP2.

Automated summary

This study reveals the molecular and cellular mechanisms of lenalidomide resistance in multiple myeloma (MM), showing that lenalidomide-resistant MM cells have enhanced extracellular vesicle (EV) secretion and adherence abilities. SORT1 and LAMP2 genes are identified as key regulators of EV secretion. Silencing of these genes decreases EV secretion and impairs cell adhesion in resistant cells, resulting in increased sensitivity to lenalidomide. Analysis of transcriptome data supports the relationship between genes related to EV secretion and adherence and patient prognosis.