Lamin B1 regulates somatic mutations and progression of B-cell malignancies

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

DOI

  • T. Klymenko, Sheffield Hallam Univ, Sheffield Hallam University, Biomed Res Ctr
  • ,
  • J. Bloehdorn, Univ Ulm, Ulm University, Dept Internal Med 3
  • ,
  • J. Bahlo, Univ Hosp Cologne, University of Cologne, Dept Internal Med 1, Ctr Integrated Oncol Cologne
  • ,
  • S. Robrecht, Univ Hosp Cologne, University of Cologne, Dept Internal Med 1, Ctr Integrated Oncol Cologne
  • ,
  • G. Akylzhanova, Queen Mary Univ, University of London, Queen Mary University London, Barts Canc Inst, Ctr Haematooncol
  • ,
  • K. Cox, Univ Southampton, University of Southampton, Expt Canc Med Ctr
  • ,
  • S. Estenfelder, Univ Ulm, Ulm University, Dept Internal Med 3
  • ,
  • J. Wang, Queen Mary Univ, University of London, Queen Mary University London, Barts Canc Inst, Ctr Haematooncol
  • ,
  • J. Edelmann, Queen Mary Univ, University of London, Queen Mary University London, Barts Canc Inst, Ctr Haematooncol
  • ,
  • J. C. Strefford, Univ Southampton, University of Southampton, Expt Canc Med Ctr
  • ,
  • T. K. Wojdacz
  • K. Fischer, Univ Hosp Cologne, University of Cologne, Dept Internal Med 1, Ctr Integrated Oncol Cologne
  • ,
  • M. Hallek, Univ Hosp Cologne, University of Cologne, Dept Internal Med 1, Ctr Integrated Oncol Cologne
  • ,
  • S. Stilgenbauer, Univ Ulm, Ulm University, Dept Internal Med 3
  • ,
  • M. Cragg, Univ Southampton, University of Southampton, Expt Canc Med Ctr
  • ,
  • J. Gribben, Queen Mary Univ, University of London, Queen Mary University London, Barts Canc Inst, Ctr Haematooncol
  • ,
  • A. Braun, Queen Mary Univ, University of London, Queen Mary University London, Barts Canc Inst, Ctr Haematooncol

Somatic hypermutation (SHM) is a pivotal process in adaptive immunity that occurs in the germinal centre and allows B cells to change their primary DNA sequence and diversify their antigen receptors. Here, we report that genome binding of Lamin B1, a component of the nuclear envelope involved in epigenetic chromatin regulation, is reduced during B-cell activation and formation of lymphoid germinal centres. Chromatin immunoprecipitation-Seq analysis showed that kappa and heavy variable immunoglobulin domains were released from the Lamin B1 suppressive environment when SHM was induced in B cells. RNA interference-mediated reduction of Lamin B1 resulted in spontaneous SHM as well as kappa-light chain aberrant surface expression. Finally, Lamin B1 expression level correlated with progression-free and overall survival in chronic lymphocytic leukaemia, and was strongly involved in the transformation of follicular lymphoma. In summary, here we report that Lamin B1 is a negative epigenetic regulator of SHM in normal B-cells and a 'mutational gatekeeper', suppressing the aberrant mutations that drive lymphoid malignancy.

Original languageEnglish
JournalLeukemia
Volume32
Issue2
Pages (from-to)364-375
Number of pages12
ISSN0887-6924
DOIs
Publication statusPublished - Feb 2018

    Research areas

  • CHRONIC LYMPHOCYTIC-LEUKEMIA, NUCLEAR LAMINA, GENE-EXPRESSION, MEMORY B, IMMUNOGLOBULIN GENES, PLASMA-CELLS, CLL8 TRIAL, HYPERMUTATION, CHROMATIN, AID

See relations at Aarhus University Citationformats

ID: 145285449