Lymphoma-associated mutations in autoreactive memory B cells of patients with Sjögren's syndrome

Richard J. Bende, Linda M. Slot, Mark J. Kwakkenbos, Thera A. M. Wormhoudt, Aldo Jongejan, Gwenny M. Verstappen, Antoine C. M. van Kampen, Jeroen E. J. Guikema, Frans G. M. Kroese, Carel J. M. van Noesel

Research output: Contribution to journalArticleAcademicpeer-review

4 Citations (Scopus)

Abstract

We recently demonstrated that normal memory B lymphocytes carry a substantial number of de novo mutations in the genome. Here, we performed exome-wide somatic mutation analyses of bona fide autoreactive rheumatoid factor (RF)-expressing memory B cells retrieved from patients with Sjӧgren's syndrome (SS). The amount and repertoire of the de novo exome mutations of RF B cells were found to be essentially different from those detected in healthy donor memory B cells. In contrast to the mutation spectra of normal B cells, which appeared random and non-selected, the mutations of the RF B cells were greater in number and enriched for mutations in genes also found mutated in B-cell non-Hodgkin lymphomas. During the study, one of the SS patients developed a diffuse large B-cell lymphoma (DLBCL) out of an RF clone that was identified 2 years earlier in an inflamed salivary gland biopsy. The successive oncogenic events in the RF precursor clone and the DLBCL were assessed. In conclusion, our findings of enhanced and selected genomic damage in growth-regulating genes in RF memory B cells of SS patients together with the documented transformation of an RF-precursor clone into DLBCL provide unique novel insight into the earliest stages of B-cell derailment and lymphomagenesis.

Original languageEnglish
Pages (from-to)264-275
Number of pages12
JournalJournal of pathology
Volume259
Issue number3
Early online date2022
DOIs
Publication statusPublished - Mar 2023

Keywords

  • B Lymphocyte
  • B cell lymphoma
  • MALT
  • Sjogren's syndrome
  • blood

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