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Homeobox NKX2-3 promotes marginal-zone lymphomagenesis by activating B-cell receptor signalling and shaping lymphocyte dynamics

Author

Listed:
  • Eloy F. Robles

    (Center for Applied Medical Research CIMA, University of Navarra)

  • Maria Mena-Varas

    (Center for Applied Medical Research CIMA, University of Navarra)

  • Laura Barrio

    (Centro Nacional de Biotecnología (CNB)-CSIC
    Present address: Dynamics of Host-Pathogen Interactions, Institut Pasteur, 25 rue du Dr Roux, 75015 Paris, France.)

  • Sara V. Merino-Cortes

    (Centro Nacional de Biotecnología (CNB)-CSIC)

  • Péter Balogh

    (Szentágothai Research Center, University of Pécs)

  • Ming-Qing Du

    (Cambridge University)

  • Takashi Akasaka

    (MRC Toxicology Unit and Ernest and Helen Scott Haematological Research Institute, University of Leicester)

  • Anton Parker

    (Royal Bournemouth Hospital)

  • Sergio Roa

    (Center for Applied Medical Research CIMA, University of Navarra)

  • Carlos Panizo

    (Clinica Universidad de Navarra)

  • Idoia Martin-Guerrero

    (Institute of Human Genetics, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Campus Kiel)

  • Reiner Siebert

    (Institute of Human Genetics, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Campus Kiel)

  • Victor Segura

    (Bio-informatic Unit, Center for Applied Medical Research CIMA, University of Navarra)

  • Xabier Agirre

    (Center for Applied Medical Research CIMA, University of Navarra)

  • Laura Macri-Pellizeri

    (Center for Applied Medical Research CIMA, University of Navarra)

  • Beatriz Aldaz

    (Center for Applied Medical Research CIMA, University of Navarra)

  • Amaia Vilas-Zornoza

    (Center for Applied Medical Research CIMA, University of Navarra)

  • Shaowei Zhang

    (Cambridge University)

  • Sarah Moody

    (Cambridge University)

  • Maria Jose Calasanz

    (School of Medicine, University of Navarra)

  • Thomas Tousseyn

    (Centre for Translation Cell and Tissue Research, KU Leuven)

  • Cyril Broccardo

    (Institut Universitaire du Cancer de Toulouse-Oncopole)

  • Pierre Brousset

    (Institut Universitaire du Cancer de Toulouse-Oncopole)

  • Elena Campos-Sanchez

    (Centro de Biologia Molecular Severo Ochoa, CSIC/Universidad Autonoma)

  • Cesar Cobaleda

    (Centro de Biologia Molecular Severo Ochoa, CSIC/Universidad Autonoma)

  • Isidro Sanchez-Garcia

    (Experimental Therapeutics and Translational Oncology Program, Institute of Molecular and Cellular Biology of Cancer, CSIC/University of Salamanca
    and Institute of Biomedical Research of Salamanca (IBSAL))

  • Jose Luis Fernandez-Luna

    (Molecular Genetics Unit, University Hospital Marques de Valdecilla and IFIMAV)

  • Ricardo Garcia-Muñoz

    (Hospital San Pedro)

  • Esther Pena

    (Complejo Hospitalario de Navarra, Servicio Navarro de Salud)

  • Beatriz Bellosillo

    (Cancer Research Program, Institut Municipal d’Investigacions Mèdiques (IMIM), Hospital del Mar)

  • Antonio Salar

    (Cancer Research Program, Institut Municipal d’Investigacions Mèdiques (IMIM), Hospital del Mar)

  • Maria Joao Baptista

    (ICO-Hospital Universitari Germans Trias i Pujol, Josep Carreras Leukaemia Research Institute, Universitat Autònoma de Barcelona)

  • Jesús Maria Hernandez-Rivas

    (IBSAL-University Hospital and IBMCC-CSIC, University of Salamanca)

  • Marcos Gonzalez

    (IBSAL-University Hospital and IBMCC-CSIC, University of Salamanca)

  • Maria Jose Terol

    (Hospital Clinico, INCLIVA Biomedical Research Institute, University of Valencia)

  • Joan Climent

    (Hospital Clinico, INCLIVA Biomedical Research Institute, University of Valencia)

  • Antonio Ferrandez

    (Hospital Clinico, University of Valencia)

  • Xavier Sagaert

    (Centre for Translation Cell and Tissue Research, KU Leuven)

  • Ari M. Melnick

    (Weill Cornell Medical College)

  • Felipe Prosper

    (Center for Applied Medical Research CIMA, University of Navarra
    Clinica Universidad de Navarra)

  • David G. Oscier

    (Royal Bournemouth Hospital)

  • Yolanda R. Carrasco

    (Centro Nacional de Biotecnología (CNB)-CSIC)

  • Martin J. S. Dyer

    (MRC Toxicology Unit and Ernest and Helen Scott Haematological Research Institute, University of Leicester)

  • Jose A. Martinez-Climent

    (Center for Applied Medical Research CIMA, University of Navarra)

Abstract

NKX2 homeobox family proteins have a role in cancer development. Here we show that NKX2-3 is overexpressed in tumour cells from a subset of patients with marginal-zone lymphomas, but not with other B-cell malignancies. While Nkx2-3-deficient mice exhibit the absence of marginal-zone B cells, transgenic mice with expression of NKX2-3 in B cells show marginal-zone expansion that leads to the development of tumours, faithfully recapitulating the principal clinical and biological features of human marginal-zone lymphomas. NKX2-3 induces B-cell receptor signalling by phosphorylating Lyn/Syk kinases, which in turn activate multiple integrins (LFA-1, VLA-4), adhesion molecules (ICAM-1, MadCAM-1) and the chemokine receptor CXCR4. These molecules enhance migration, polarization and homing of B cells to splenic and extranodal tissues, eventually driving malignant transformation through triggering NF-κB and PI3K-AKT pathways. This study implicates oncogenic NKX2-3 in lymphomagenesis, and provides a valid experimental mouse model for studying the biology and therapy of human marginal-zone B-cell lymphomas.

Suggested Citation

  • Eloy F. Robles & Maria Mena-Varas & Laura Barrio & Sara V. Merino-Cortes & Péter Balogh & Ming-Qing Du & Takashi Akasaka & Anton Parker & Sergio Roa & Carlos Panizo & Idoia Martin-Guerrero & Reiner Si, 2016. "Homeobox NKX2-3 promotes marginal-zone lymphomagenesis by activating B-cell receptor signalling and shaping lymphocyte dynamics," Nature Communications, Nature, vol. 7(1), pages 1-16, September.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11889
    DOI: 10.1038/ncomms11889
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