Department of Molecular and Cellular Medicine, Institute of Medical Science, Tokyo Medical University, Tokyo, Japan.
Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan.
Blood Adv. 2022 Apr 26;6(8):2480-2495. doi: 10.1182/bloodadvances.2021005772.
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.
多发性骨髓瘤（MM）是一种血液恶性肿瘤，在过去十年中，随着来那度胺等新药物的发展，其预后得到了改善。然而，长期暴露于药物会导致 MM 细胞获得耐药性，从而导致治疗失败和预后不良。在这里，我们展示了 MM 中来那度胺耐药的分子和细胞机制。在来那度胺耐药细胞系与亲本细胞系的比较中，耐药细胞中外泌体（EV）分泌和黏附能力显著升高。全转录组分析显示，SORT1 和 LAMP2 基因是 EV 分泌的关键调节因子。这些基因的沉默导致耐药细胞中 EV 分泌减少和细胞黏附丧失，从而增加对来那度胺的敏感性。对公开可用的转录组数据的分析证实了与 EV 分泌和细胞黏附相关的基因与患者预后之间的关系。总之，我们的研究结果揭示了一种通过 SORT1 和 LAMP2 介导的 EV 分泌和细胞黏附的 MM 中来那度胺耐药的新机制。
