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

KLYMENKO, Tetyana, BLOEHDORN, J, BAHLO, J, ROBRECHT, S, AKYLZHANOVA, G, COX, K, ESTENFELDER, S, WANG, J, EDELMANN, J, STREFFORD, J C, WOJDACZ, T K, FISCHER, K, HALLEK, M, STILGENBAUER, S, CRAGG, M, GRIBBEN, J and BRAUN, A (2018). Lamin B1 regulates somatic mutations and progression of B-cell malignancies. Leukemia, 32 (2), 364-375.

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    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.

    Item Type: Article
    Research Institute, Centre or Group - Does NOT include content added after October 2018: Biomolecular Sciences Research Centre
    Identification Number:
    Page Range: 364-375
    Depositing User: Eddy Verbaan
    Date Deposited: 26 Oct 2017 13:45
    Last Modified: 18 Mar 2021 15:21

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