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Lymphoma

De novo gene mutations in normal human memory B cells

Abstract

In the past years, the genomes of thousands of tumors have been elucidated. To date however, our knowledge on somatic gene alterations in normal cells is very limited. In this study, we demonstrate that tetanus-specific human memory B lymphocytes carry a substantial number of somatic mutations in the coding regions of the genome. Interestingly, we observed a statistically significant correlation between the number of exome mutations and those present in the immunoglobulin heavy variable regions. Our findings indicate that the majority of these genomic mutations arise in an antigen-dependent fashion, most likely during clonal expansion in germinal centers. The knowledge that normal B cells accumulate genomic alterations outside the immunoglobulin loci during development is relevant for our understanding of the process of lymphomagenesis.

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Acknowledgements

We thank Berend Hooibrink, Toni van Capel and Kim Brandwijk for FACS-sorting. We thank Susan Cuvalay for help in organizing donor material of hyperimmunized tetanus donors from Sanquin, Amsterdam, The Netherlands. We thank Martin Haagmans for performance of parts of the whole-exome sequence alignments. This research was supported by a Dutch Cancer Society grant (UVA 2009–4525) and a grant from the Dutch Artritis Foundation (2015–2–310).

Author contributions

L.M.S., R.J.B., and C.J.M.v.N. designed the research; L.M.S., T.A.M.W., M.J.K., K.W., A.B., and R.J.B. performed the research; L.M.S., A.J., A.H.C.v.K., J.E.J.G., R.J.B., and C.J.M.v.N. analyzed the data; L.M.S., R.J.B., and C.J.M.v.N. wrote the manuscript; and all authors edited the manuscript.

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Correspondence to C. J. M. van Noesel.

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Slot, L.M., Wormhoudt, T.A.M., Kwakkenbos, M.J. et al. De novo gene mutations in normal human memory B cells. Leukemia 33, 1219–1230 (2019). https://doi.org/10.1038/s41375-018-0289-4

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