ScRNA-sequencing uncovers metabolism and CD52 as new targets in ibrutinib-surviving mantle cell lymphoma cells

Abstract

Ibrutinib improves the treatment of relapsed or refractory mantle cell lymphoma, amature Bcell neoplasm. However, relapses following treatment with this Bruton tyrosine kinase inhibitor occur frequently, and the outcome of affected patients is poor. Single-cell RNA sequencing (scRNA-seq) can track trends in gene expression of mantle cell lymphoma cells across ibrutinib treatment and new therapeutic targets can be defined based on the detected resistance mechanisms. The ibrutinib-sensitive mantle cell lymphoma cell line REC‑1 was treated with ibrutinib for6 h and48 h. Droplet-based scRNA-seq was performed to examine the transcriptomic alterations of surviving cells using the 10×Genomics platform. Extracellular flux analysis and flow cytometry were applied to further study the observed adaptations to ibrutinib treatment. REC‑1 harbored asubpopulation with potential for crosstalk with microenvironment and therefore greater risk for aggressiveness and drug resistance. Following ibrutinib treatment, NF-κB signaling was turned off. In contrast, the cells upregulated B-cell receptor genes and surface antigens such as CD52, and switched their metabolism to increased dependence on oxidative phosphorylation. Targeting oxidative phosphorylation or CD52 in combination with or as follow-up to ibrutinib might overcome resistance and provide improved prognosis for mantle cell lymphoma patients.