Journal
LEUKEMIA
Volume 32, Issue 2, Pages 364-375Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2017.255
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Funding
- Kay Kendall Leukemia Fund [KKL1101]
- Cancer Research UK Centre Grant [C16420/A18066]
- DFG [SFB1074 B2]
- EC TransCan (FIRE CLL)
- BMBF (PRECISE)
- German Research Foundation [ED 256/1-1]
- Bloodwise [11052, 12036]
- Kay Kendall Leukaemia Fund [873]
- Cancer Research UK [C34999/A18087, ECMC C24563/A15581]
- Wessex Medical Research
- Bournemouth Leukaemia Fund
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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.
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