Quantitative Proteomics Reveals the Role of Lysine Lactylation in Lenalidomide-Resistance in Multiple Myeloma Cells [CUT&Tag]

Multiple myeloma (MM) is a hematologic malignancy characterized by abnormal plasma cell proliferation, with lenalidomide emerging as a primary treatment. However, prolonged use often leads to drug resistance, underscoring the need to understand resistance mechanisms. Protein post-translational modifications (PTMs) play crucial roles in disease development, including chemoresistance. Here, we investigate the involvement of new types of PTMs, focusing on lysine lactylation (Kla), in lenalidomide resistance. We observed elevated Kla levels in lenalidomide-resistant MM cells, implicating its role in resistance. Through quantitative proteome, lactylome, and acetylome analysis, we identified 7493 proteins, 1241 Kla sites, and 9313 lysine acetylation (Kac) sites, thereby revealing differential protein expression and PTM profiles in lenalidomide-resistant cells. Proteomic analysis revealed that a serious of chemoresistance related proteins were upregulated, and a number of CRL4-CRBN regulatory factors were downregulated. Lactylome analysis revealed that numerous chemoresistance related proteins exhibited increased Kla levels in lenalidomide-resistant MM cells, suggesting that Kla played an important role in the development of lenalidomide-resistance in LenR MM cells. Notably, histone H4K8la were associated with upregulation of chemoresistance-related genes CDK6 and ECHS1. Our findings shed light on the epigenetic mechanisms underlying lenalidomide resistance in MM, offering insights for overcoming chemoresistance.