Clipson, A., Wang, M., de Leval, L., Ashton-Key, M., Wotherspoon, A., Vassiliou, G., Bolli, N., Grove, C., Moody, S., Escudero-Ibarz, L., Gundem, G., Brugger, K., Xue, X., Mi, E., Bench, A., Scott, M., Liu, H., Follows, G., Robles, E. F., Martinez-Climent, J. A., Oscier, D., Watkins, A. J., Du, M. Q. (2015) KLF2 mutation is the most frequent somatic change in splenic marginal zone lymphoma and identifies a subset with distinct genotype. LEUKEMIA, 29 (5). pp. 1177-1185. ISSN 0887-6924

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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-.B 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.

Item Type:	Article
All Authors:	Clipson, A., Wang, M., de Leval, L., Ashton-Key, M., Wotherspoon, A., Vassiliou, G., Bolli, N., Grove, C., Moody, S., Escudero-Ibarz, L., Gundem, G., Brugger, K., Xue, X., Mi, E., Bench, A., Scott, M., Liu, H., Follows, G., Robles, E. F., Martinez-Climent, J. A., Oscier, D., Watkins, A. J., Du, M. Q.
Additional Information:	ISI Document Delivery No.: CH5JA Times Cited: 0 Cited Reference Count: 52 Clipson, A. Wang, M. de Leval, L. Ashton-Key, M. Wotherspoon, A. Vassiliou, G. Bolli, N. Grove, C. Moody, S. Escudero-Ibarz, L. Gundem, G. Brugger, K. Xue, X. Mi, E. Bench, A. Scott, M. Liu, H. Follows, G. Robles, E. F. Martinez-Climent, J. A. Oscier, D. Watkins, A. J. Du, M-Q Leukaemia and Lymphoma Research, UK, Addenbrooke's Charitable Trust; MRC; Department of Pathology, University of Cambridge; Pathological Society of UK; Pathological Society of Ireland; Academy of Medical Sciences 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. 0 NATURE PUBLISHING GROUP LONDON LEUKEMIA
Uncontrolled Keywords:	KRUPPEL-LIKE FACTOR-2 ADNEXAL MALT LYMPHOMA B-CELL DEVELOPMENT VILLOUS LYMPHOCYTES NOTCH2 INFLAMMATION EXPRESSION DELETION RECEPTOR GENES
Research teams:	Clinical Units > Department of Histopathology
Depositing User:	Barry Jenkins
Date Deposited:	29 May 2015 13:30
Last Modified:	29 May 2015 13:30
URI:	http://publications.icr.ac.uk/id/eprint/14141

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