[scRNA-sequencing uncovers metabolism and CD52 as new targets in ibrutinib-surviving mantle cell lymphoma cells].

Abstract

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.

• Authors: Viktoria Fuhr, Ehsan Vafadarnejad, Oliver Dietrich, Panagiota Arampatzi, Angela Riedel, Antoine-Emmanuel Saliba, Andreas Rosenwald, Hilka Rauert-Wunderlich
• Journal: Pathologie (Heidelberg, Germany) (Pathologie (Heidelb)) Vol. 43 Issue Suppl 1 Pg. 31-35 (Aug 2022) ISSN: 2731-7196 [Electronic] Germany
• Vernacular Title: Eine Einzelzell-RNA-Sequenzierung identifiziert Metabolismus und CD52 als neue Angriffspunkte in Ibrutinib-persistenten Mantelzelllymphomzellen.
• PMID: 36222922 (Publication Type: English Abstract, Journal Article)
• Copyright: © 2022. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.

Chemical References

• Agammaglobulinaemia Tyrosine Kinase
• CD52 Antigen
• CD52 protein, human
• ibrutinib
• Pyrazoles
• Pyrimidines
• RNA, Small Cytoplasmic

Topics

• Humans
• Agammaglobulinaemia Tyrosine Kinase (genetics)
• CD52 Antigen
• Lymphoma, Mantle-Cell (drug therapy)
• Neoplasm Recurrence, Local (chemically induced)
• Pyrazoles (pharmacology)
• Pyrimidines (pharmacology)
• RNA, Small Cytoplasmic
• Single-Cell Analysis
• Tumor Microenvironment (genetics)