CSNK1E sustains stemlike drug persistence in diffuse large B-cell lymphoma
Abstract
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, and identifies CSNK1E as a critical mediator and therapeutic vulnerability that may improve the efficacy of standard immunochemotherapy in DLBCL.
Article Details
Authors (18)
Xiang Li
Mengke Liu
Qing Shi
1Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai, China
Zhi-Shan Du
1Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai, China
Di Fu
Ying Fang
Liang-Juan Zhao
1Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai, China
Yuting Dai
Mu-Chen Zhang
1Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai, China
Fan Zhang
Yan Zhao
Hong-Mei Yi
2Department of Pathology, Ruijin Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai, China
Yang He
Shu Cheng
Peng-Peng Xu
1Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai, China
Li Wang
The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital Zhengzhou China
Jiahao Chen
Spin-X Institute, School of Chemistry and Chemical Engineering, School of Biomedical Sciences and Engineering, Guangdong-Hong Kong-Macao Joint Laboratory of Optoelectronic and Magnetic Functional Materials, State Key Laboratory of Luminescent Materials and Devices
Wei-Li Zhao
1Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China