Relapsed or refractory (R/R) disease occurs in up to 40% of diffuse large B-cell lymphoma (DLBCL) patients following first-line immunochemotherapy. However the molecular mechanisms underlying drug persistence remain incompletely defined. Here, we performed single-cell RNA and B-cell receptor sequencing on paired diagnostic and R/R samples from eight patients who were either treatment-refractory or relapsed after remission, and validated our findings in three 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 stem-like 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 CSNK1E was upregulated in these stem-like drug-persistent cells, in part through the activation of the APRIL-TNFRSF13B axis. Notably, CSNK1E inhibition impaired the growth and tumor-initiating capacity of drug-persistent cells and potentiated the efficacy of R-CHOP-based treatment both in vitro and in vivo. Together, our study reveals the stem-like transcriptional and functional properties of drug-persistent cells, and identifies CSNK1E as a critical mediator and therapeutic vulnerability to improve the efficacy of standard immunochemotherapy in DLBCL.
Li et al. (2026) studied this question.