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

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 Siebert, Victor Segura, Xabier Agirre, Laura Macri-Pellizeri, Beatriz Aldaz, Amaia Vilas-Zornoza, Shaowei Zhang, Sarah Moody, Maria Jose Calasanz, Thomas Tousseyn, Cyril Broccardo, Pierre Brousset, Elena Campos-Sanchez, Cesar Cobaleda, Isidro Sanchez-Garcia, Jose Luis Fernandez-Luna, Ricardo Garcia-Muñoz, Esther Pena, Beatriz Bellosillo, Antonio Salar, Maria Joao Baptista, Jesús Maria Hernandez-Rivas, Marcos Gonzalez, Maria Jose Terol, Joan Climent, Antonio Ferrandez, Xavier Sagaert, Ari M. Melnick, Felipe Prosper, David G. Oscier, Yolanda R. Carrasco, Martin J. S. Dyer and Jose A. Martinez-Climent ()
Additional contact information
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
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
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
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

Nature Communications, 2016, vol. 7, issue 1, 1-16

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms11889

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