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Chronic Lymphocytic Leukemia

Distinct patterns of novel gene mutations in poor-prognostic stereotyped subsets of chronic lymphocytic leukemia: the case of SF3B1 and subset #2

Leukemia volume 27, pages 2196–2199 (2013)Cite this article

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Abstract

Recent studies have revealed recurrent mutations of the NOTCH1, SF3B1 and BIRC3 genes in chronic lymphocytic leukemia (CLL), especially among aggressive, chemorefractory cases. Nevertheless, it is currently unknown whether their presence may differ in subsets of patients carrying stereotyped B-cell receptors and also exhibiting distinct prognoses. Here, we analyzed the mutation status of NOTCH1, SF3B1 and BIRC3 in three subsets with particularly poor prognosis, that is, subset #1, #2 and #8, aiming to explore links between genetic aberrations and immune signaling. A remarkably higher frequency of SF3B1 mutations was revealed in subset #2 (44%) versus subset #1 and #8 (4.6% and 0%, respectively; P<0.001). In contrast, the frequency of NOTCH1 mutations in subset #2 was only 8%, lower than the frequency observed in either subset #1 or #8 (19% and 14%, respectively; P=0.04 for subset #1 versus #2). No associations were found for BIRC3 mutations that overall were rare. The apparent non-random association of certain mutations with stereotyped CLL subsets alludes to subset-biased acquisition of genomic aberrations, perhaps consistent with particular antigen/antibody interactions. These novel findings assist in unraveling specific mechanisms underlying clinical aggressiveness in poor-prognostic stereotyped subsets, with far-reaching implications for understanding their clonal evolution and implementing biologically oriented therapy.

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Acknowledgements

This research was supported by the Nordic Cancer Union, the Swedish Cancer Society, the Swedish Research Council and the Lion’s Cancer Research Foundation, Uppsala, Sweden; Associazione Italiana per la Ricerca sul Cancro (AIRC) (Investigator grant and Molecular Clinical Oncology Program 5xMille no. 9965), Milano, Italy; Ricerca Finalizzata 2010, Ministero della Salute, Roma, Italy; PRIN, MIUR, Roma, Italy; Leukaemia and Lymphoma Research, UK; The Kay Kendell Leukaemia Fund, London, UK; ENosAI project (code 09SYN-13-880) co-funded by the EU and the Hellenic General Secretariat for Research and Technology, Athens, Greece; The NIH/National Cancer Institute (RO1 Grant CA081554), Bethesda, MD, USA; IGA MZ CR NT13493-4/2012 and MSMT CR projects CZ.1.05/1.1.00/02.0068 (CEITEC) and CZ.1.07/2.3.00/20.0045 (SuPReMMe). We thank Jana Kminkova, Barbara Kantorova, Veronika Navrkalova and Hana Skuhrova Francova for their intensive and enthusiastic help with DNA analyses.

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Author notes

  1. J C Strefford, L-A Sutton and P Baliakas: Contributed equally as first authors.

  2. P Ghia, K Stamatopoulos and R Rosenquist: Contributed equally as senior authors.

Authors and Affiliations

  1. Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK

    J C Strefford

  2. Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Sweden

    L-A Sutton, P Baliakas, D Cortese, N Cahill, L Mansouri & R Rosenquist

  3. Hematology Department and HCT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece

    P Baliakas, E Stalika & K Stamatopoulos

  4. Division of Molecular Oncology and Department of Onco-Hematology, Istituto Scientfico San Raffaele e Fondazione Centro San Raffaele, Milano, Italy

    A Agathangelidis, L Scarfó & P Ghia

  5. Università Vita-Salute San Raffaele, Milano, Italy

    A Agathangelidis, L Scarfó & P Ghia

  6. Central European Institute of Technology, Masaryk University and University Hospital, Brno, Czech Republic

    J Malčíková, K Plevova & S Pospisilova

  7. Department of Molecular Pathology, Royal Bournemouth Hospital, Bournemouth, UK

    Z Davis & D Oscier

  8. Department of Hematology, Leukemia Laboratory, Rigshospitalet, Copenhagen, Denmark

    L B Pedersen & C Geisler

  9. CERMS, S. Giovanni Battista Hospital, Turin, Italy

    P F di Celle

  10. First Department of Propaedeutic Medicine, School of Medicine, University of Athens, Athens, Greece

    T Tzenou & P Panagiotidis

  11. Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands

    A W Langerak

  12. The Karches Center for Chronic Lymphocytic Leukemia Research, The Feinstein Institute for Medical Research, Manhasset, NY, USA

    N Chiorazzi

  13. Laboratory of Hematology and Universite Pierre et Marie Curie, Hopital Pitie-Salpetriere, Paris, France

    F Davi

  14. Hematology Department, Nikea General Hospital, Pireaus, Greece

    C Belessi

  15. Institute of Applied Biosciences, Center for Research and Technology Hellas, Thessaloniki, Greece

    K Stamatopoulos

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  1. J C Strefford
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Strefford, J., Sutton, LA., Baliakas, P. et al. Distinct patterns of novel gene mutations in poor-prognostic stereotyped subsets of chronic lymphocytic leukemia: the case of SF3B1 and subset #2. Leukemia 27, 2196–2199 (2013). https://doi.org/10.1038/leu.2013.98

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