Pathologie (Heidelberg, Germany) · 2022
[scRNA-sequencing uncovers metabolism and CD52 as new targets in ibrutinib-surviving mantle cell lymphoma cells].
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Fuhr Viktoria, Vafadarnejad Ehsan, Dietrich Oliver, Arampatzi Panagiota, Riedel Angela, Saliba Antoine-Emmanuel, Rosenwald Andreas, Rauert-Wunderlich Hilka
Аннотация
BACKGROUND: Ibrutinib improves the treatment of relapsed or refractory mantle cell lymphoma, a mature B cell neoplasm. However, relapses following treatment with this Bruton tyrosine kinase inhibitor occur frequently, and the outcome of affected patients is poor.
OBJECTIVES: 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.
MATERIALS AND METHODS: The ibrutinib-sensitive mantle cell lymphoma cell line REC‑1 was treated with ibrutinib for 6 h and 48 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.
RESULTS: REC‑1 harbored a subpopulation 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.
CONCLUSIONS: 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.
OBJECTIVES: 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.
MATERIALS AND METHODS: The ibrutinib-sensitive mantle cell lymphoma cell line REC‑1 was treated with ibrutinib for 6 h and 48 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.
RESULTS: REC‑1 harbored a subpopulation 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.
CONCLUSIONS: 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.