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The Krüppel-like factor 2 transcription factor gene is recurrently mutated in splenic marginal zone lymphoma

Leukemia volume 29, pages 503–507 (2015)Cite this article

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Splenic marginal zone lymphoma (SMZL) is an indolent B-cell tumor involving the spleen, and is characterized by recurrent deletion of chromosome 7q and biased usage of the immunoglobulin heavy variable (IGHV) allele 1-2*04.1 Genomic studies have partially unraveled the typical SMZL-coding genome, which is characterized by lesions affecting genes involved in the physiological homeostasis of marginal zone (MZ) B cells, including mutations of NOTCH2.2, 3, 4, 5 However, the full spectrum of lesions that contribute to the malignant transformation of SMZL remains unknown.

Overall, 80 KLF2 mutations were identified (Supplementary Table S3). Of these, 26% (n=21) were truncating mutations (frameshift indels=12; nonsense substitutions=5; splice-site variants=4) (Figure 1b). By complementary DNA analysis, splice-site mutations caused aberrant transcripts that retained intronic sequences and lost their coding potential. On the basis of their distribution along KLF2, truncating mutations were predicted to either disrupt the entire protein or to remove the zinc-finger (ZnF) domains of KLF2, including the putative nuclear localization signal (NLS) sequences (Figure 1c).8, 9, 10 Missense mutations (n=55) and in frame indels (n=4) accounted for 74% of the variants (Figure 1b). According to PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/), the majority of KLF2 missense substitutions were predicted to be deleterious (Supplementary Table S3). A large fraction of the missense mutations (n=27) clustered in the region encoding the first two ZnFs of KLF2, suggesting that they may affect its nuclear localization, as well as the transcriptional function of the protein (Figure 1c).8, 9, 10, 11 Notably, amino-acid changes recurrently affected evolutionarily conserved codons of the first ZnF, including recurrent substitutions at positions 288 (n=9) and 291 (n=5), which are involved in DNA recognition by KLF2 (Supplementary Figure S1).11 The 5′ basic NLS of KLF2, which maps before the ZnF, was also recurrently targeted by missense substitutions (n=7) (Figure 1c).8, 9, 10, 11 The remaining missense mutations distributed in the N-terminal activation domain (n=7, including three somatic mutations targeting a hotspot at codon 37) and in the inhibitory domain (n=14) (Figure 1c).9, 10 Targeted next generation sequencing analysis revealed that KLF2 mutations (assessable=42) were clonally represented in the tumor (median variant allele frequency=35%) (Figure 1d). Whenever possible, complementary DNA sequencing confirmed that KLF2 mutations (n=21) were always expressed at the transcript level (Supplementary Figure S2). The somatic origin of mutations was confirmed in all tested cases by analysis of paired normal DNA, which was available for most of the variants (n=52, including 36 missense substitutions) (Figure 1c; Supplementary Table S3). Most (72%; 41/57) lymphoma cases harbored one single monoallelic KLF2 mutation. Among the cases displaying more than one mutational event, sequencing analysis of KLF2 transcripts after subcloning demonstrated that the mutations were generally (60%) located on separate alleles. Beside KLF2, no other KLF family member homologous to KLF2, nor genes belonging to the KLF2 pathway were mutated in SMZL (Supplementary Table S1).

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Acknowledgements

This study was supported by: Special Program Molecular Clinical Oncology 5 x 1000 No. 10007, My First AIRC Grant No. 13470, and Investigator Grant IG-13227, Associazione Italiana per la Ricerca sul Cancro (AIRC) Foundation Milan, Italy; Fondazione Cariplo, Grant No. 2012-0689; Progetto Giovani Ricercatori 2010, Grant No. GR-2010-2317594, Ministero della Salute, Rome, Italy; Compagnia di San Paolo, Grant No. PMN_call_2012_0071, Turin, Italy; Futuro in Ricerca 2012 Grant No. RBFR12D1CB, Ministero dell'Istruzione, dell'Università e della Ricerca, Rome, Italy; Nelia et Amadeo Barletta Foundation, Lausanne, Switzerland.

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Author notes

  1. R Piva and S Deaglio: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular Biotechnology and Health Sciences Biology and Biochemistry, Molecular Biotechnology Center, University of Turin and Human Genetics Foundation, Turin, Italy,

    R Piva, I Scarfò, E Mereu & G Garaffo

  2. Department of Medical Sciences, University of Turin and Human Genetics Foundation, Turin, Italy

    S Deaglio, R Buonincontri, S Serra, D Brusa & G Inghirami

  3. Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy

    R Famà, A Bruscaggin, V Spina, S Monti, G Gaidano & D Rossi

  4. Clinical and Experimental Onco-Hematology, CRO, IRCCS, Aviano, Italy

    M Dal Bo & V Gattei

  5. Division of Hematology, University of Modena and Reggio Emilia, Modena, Italy

    R Marasca

  6. Divisions of Hematology, University of Pavia, Pavia, Italy

    L Arcaini

  7. Department of Clinical Sciences and Community Health, University of Milano and Hematology 1 CTMO, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy

    A Neri

  8. Fondazione IRCCS Policlinico San Matteo & Department of Molecular Medicine, Pathology, University of Pavia, Pavia, Italy

    M Paulli

  9. Institute of Hematology, University of Perugia, Perugia, Italy

    E Tiacci

  10. Lymphoma and Genomics Research Program, IOR Institute of Oncology Research and Oncology Institute of Southern Switzerland, Bellinzona, Switzerland

    F Bertoni

  11. Haematopathology, L. & A. Seragnoli Institute, University of Bologna, Bologna, Italy

    S A Pileri

  12. Division of Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy

    R Foà

  13. Department of Pathology and New York University Cancer Center, New York University School of Medicine, New York, NY, USA,

    G Inghirami

  14. Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA

    G Inghirami

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  1. R Piva
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Correspondence to D Rossi.

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Piva, R., Deaglio, S., Famà, R. et al. The Krüppel-like factor 2 transcription factor gene is recurrently mutated in splenic marginal zone lymphoma. Leukemia 29, 503–507 (2015). https://doi.org/10.1038/leu.2014.294

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