DKC1：多发性骨髓瘤中一个稳健的预后因子和潜在治疗靶点

Abstract

Background Multiple myeloma (MM) is an incurable plasma cell malignancy. Dyskerin pseudouridine synthase 1 (DKC1), a nucleolar protein, is essential for RNA modification and cellular homeostasis, yet its role in MM remains unclear. Methods Prognostic significance of DKC1 in MM patients was evaluated using the MMRF CoMMpass and GEO datasets. Functional effects of DKC1 knockdown or overexpression were investigated via in vitro proliferation, apoptosis assays and in vivo xenografts. Transcriptomic profiling and CMC-based pseudouridine (Ψ) mapping were used to define DKC1-mediated regulation of ATF5. Results Elevated DKC1 expression was identified as an independent prognostic marker of poor outcomes in MM patients. Decision tree analysis demonstrated that integrating DKC1 expression further refined prognostic stratification beyond the ISS system. Functional assays revealed that DKC1 promoted MM cell proliferation, survival and colony formation, while DKC1 knockdown or pharmacologic inhibition with pyrazofurin significantly reduced MM cell proliferation and colony formation, increased apoptosis in vitro, and suppressed tumor growth in xenograft models. RNA sequencing analysis identified ATF5 as a downstream target of DKC1, and subsequent experimental validation confirmed that DKC1 exerts part of its function through ATF5. We further demonstrated that DKC1 knockdown reduces ATF5 mRNA stability through impaired pseudouridylation. Site-specific Ψ modifications on ATF5 mRNA confirmed a direct post-transcriptional regulatory mechanism. Conclusions DKC1 drives MM progression by promoting ATF5 stability through pseudouridylation, thereby enhancing myeloma cell proliferation and survival. These findings highlight that DKC1 may be used as a potential biomarker for risk stratification and a promising therapeutic target in MM.