CSNK1E sustains stemlike drug persistence in diffuse large B-cell lymphoma

作者：X Li, Mengke Liu, Qing Shi, Zhi-Shan Du, Di Fu, Ying Fang, Liang-Juan Zhao, Yuting Dai, Mu‐Chen Zhang, Fan Zhang, Yan Zhao, Hong-Mei Yi, Y Yiannian He, Shu Cheng, Peng-Peng Xu, Li Wang, Jiahao Chen, Wei-Li Zhao · 发表于：Blood · 年份：2026 · DOI：10.1182/blood.2025031156 · 被引用次数：2 · 研究领域：Lymphoma Diagnosis and Treatment、CAR-T cell therapy research、CNS Lymphoma Diagnosis and Treatment

ABSTRACT: Relapsed or refractory (R/R) disease occurs in up to 40% of patients with diffuse large B-cell lymphoma (DLBCL) following first-line immunochemotherapy. However, the molecular mechanisms underlying drug persistence remain incompletely defined. In this study, we performed single-cell RNA and B-cell receptor sequencing on paired diagnostic and R/R samples from 8 patients who were either treatment-refractory or relapsed after remission, and validated our findings in 3 independent patient cohorts. We found that drug-persistent cells exhibited a transcriptional profile indicative of a less-differentiated state and adopted a memory B-cell-like program with enhanced stemlike properties, which correlated with unfavorable clinical outcomes across multiple DLBCL cohorts. Functionally, drug-persistent cells showed significantly increased in vitro clonogenicity and in vivo tumor-initiating capacity. Mechanistically, the WNT signaling regulator casein kinase 1ɛ (CSNK1E) was upregulated in these stemlike drug-persistent cells, in part through the activation of the A proliferation-inducing ligand (APRIL)-TNFRSF13B axis. Notably, CSNK1E inhibition impaired the growth and tumor-initiating capacity of drug-persistent cells and potentiated the efficacy of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone)-based treatment, both in vitro and in vivo. Together, our study reveals the stemlike transcriptional and functional properties of drug-persistent cells, a...