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Lymphoma

KLF2 mutation is the most frequent somatic change in splenic marginal zone lymphoma and identifies a subset with distinct genotype

Leukemia volume 29, pages 1177–1185 (2015)Cite this article

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Abstract

To characterise the genetics of splenic marginal zone lymphoma (SMZL), we performed whole exome sequencing of 16 cases and identified novel recurrent inactivating mutations in Kruppel-like factor 2 (KLF2), a gene whose deficiency was previously shown to cause splenic marginal zone hyperplasia in mice. KLF2 mutation was found in 40 (42%) of 96 SMZLs, but rarely in other B-cell lymphomas. The majority of KLF2 mutations were frameshift indels or nonsense changes, with missense mutations clustered in the C-terminal zinc finger domains. Functional assays showed that these mutations inactivated the ability of KLF2 to suppress NF-κB activation by TLR, BCR, BAFFR and TNFR signalling. Further extensive investigations revealed common and distinct genetic changes between SMZL with and without KLF2 mutation. IGHV1-2 rearrangement and 7q deletion were primarily seen in SMZL with KLF2 mutation, while MYD88 and TP53 mutations were nearly exclusively found in those without KLF2 mutation. NOTCH2, TRAF3, TNFAIP3 and CARD11 mutations were observed in SMZL both with and without KLF2 mutation. Taken together, KLF2 mutation is the most common genetic change in SMZL and identifies a subset with a distinct genotype characterised by multi-genetic changes. These different genetic changes may deregulate various signalling pathways and generate cooperative oncogenic properties, thereby contributing to lymphomagenesis.

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Acknowledgements

We would like to thank David Withers for his help in DNA sequencing, and Dr Yuanxue Huang, Howard Martin, Antje Schulze Selting and Robbie Zhao for technical assistance. We would also like to thank NIHR Cambridge Comprehensive Biomedical Research Centre Tissue and Blood Biobank for providing some of the lymphoma samples used in this study. This research was supported by grants from Leukaemia and Lymphoma Research, UK, Addenbrooke’s Charitable Trust. SM is a PhD student supported by MRC and Department of Pathology, University of Cambridge. LEI is a PhD student supported by the Pathological Society of UK and Ireland. NB is a fellow of the European Hematology Association and was supported by a starter grant from the Academy of Medical Sciences.

Author Contributions

AC, MW, SM, LE-I, EM, HL, EFR, GV, JAM-C and DO contributed to data collection and analysis; AC, NB, CG, GG, KB and XX contributed to sequence analysis; LdL, MA-K, AW, GV, AB, MS, GF, JAM-C and DO helped in case contribution; M-QD, AC and MW contributed to manuscript writing and preparation; M-QD and AJW contributed to study design and coordination. All authors commented on the manuscript and approve its submission for publication.

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  1. A Clipson and M Wang: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Molecular Histopathology, Department of Pathology, University of Cambridge, Cambridge, UK

    A Clipson, M Wang, S Moody, L Escudero-Ibarz, X Xue, E Mi, A J Watkins & M-Q Du

  2. Institute of Pathology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland

    L de Leval

  3. Department of Cellular Pathology, Southampton University Hospitals National Health Service Trust, Southampton, UK

    M Ashton-Key

  4. Department of Histopathology, Royal Marsden Hospital, London, UK

    A Wotherspoon

  5. Wellcome Trust Sanger Institute, Cambridge, Hinxton, UK

    G Vassiliou, N Bolli, C Grove & G Gundem

  6. Department of Haematology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK

    G Vassiliou, N Bolli, A Bench, M Scott, G Follows & A J Watkins

  7. Department of Molecular Genetics, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK

    K Brugger

  8. Molecular Malignancy Laboratory, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK

    H Liu

  9. Division of Oncology, Center for Applied Medical Research CIMA, University of Navarra, Pamplona, Spain

    E F Robles & J A Martinez-Climent

  10. Department of Haematology, Royal Bournemouth Hospital, Bournemouth, UK

    D Oscier

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  1. A Clipson
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Correspondence to M-Q Du.

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Clipson, A., Wang, M., de Leval, L. et al. KLF2 mutation is the most frequent somatic change in splenic marginal zone lymphoma and identifies a subset with distinct genotype. Leukemia 29, 1177–1185 (2015). https://doi.org/10.1038/leu.2014.330

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