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

Area of Science:

• Hematology
• Oncology
• Molecular Biology

Background:

• Relapsed or refractory (R/R) disease affects up to 40% of diffuse large B-cell lymphoma (DLBCL) patients post-immunochemotherapy.
• Molecular mechanisms of drug persistence in DLBCL are not fully understood.

Purpose of the Study:

• To investigate the molecular and functional characteristics of drug-persistent cells in DLBCL.
• To identify potential therapeutic targets to overcome treatment resistance in DLBCL.

Main Methods:

• Single-cell RNA and B-cell receptor sequencing on paired diagnostic and R/R DLBCL samples.
• Validation in three independent patient cohorts.
• In vitro and in vivo functional assays and mechanistic studies.

Main Results:

• Drug-persistent DLBCL cells display a less-differentiated, stem-like phenotype with memory B cell characteristics.
• These stem-like cells exhibit increased clonogenicity and tumor-initiating capacity, correlating with poor outcomes.
• Upregulation of CSNK1E, driven by the APRIL-TNFRSF13B axis, was identified in stem-like cells.
• CSNK1E inhibition reduced tumor growth and enhanced R-CHOP treatment efficacy.

Conclusions:

• Drug-persistent DLBCL cells possess stem-like properties contributing to treatment failure.
• CSNK1E is a critical mediator of drug persistence and a potential therapeutic target.
• Targeting CSNK1E may improve outcomes for R/R DLBCL patients treated with standard immunochemotherapy.