Homeobox NKX2-3 promotes marginal-zone lymphomagenesis by activating B-cell receptor signalling and shaping lymphocyte dynamics
Robles EF (1), Mena-Varas M (1), Barrio L (2), Merino-Cortes SV (2), Balogh P (3), Du MQ (4), Akasaka T (5), Parker A (6), Roa S (1), Panizo C (7), Martin-Guerrero I (8), Siebert R (8), Segura V (9), Agirre X (1), Macri-Pellizeri L (1), Aldaz B (1), Vilas-Zornoza A (1), Zhang S (4), Moody S (4), Calasanz MJ (10), Tousseyn T (11), Broccardo C (12), Brousset P (12), Campos-Sanchez E (13), Cobaleda C (13), Sanchez-Garcia I (14), Fernandez-Luna JL (15), Garcia-Muñoz R (16), Pena E (17), Bellosillo B (18), Salar A (19), Baptista M J (20), Hernandez-Rivas JM (21), Gonzalez M (21), Terol MJ (22), Climent J (22), Ferrandez A (23), Sagaert X (11), Melnick AM (24), Prosper F (1,7), Oscier DG (6), Carrasco YR (2), Dyer MJ (5), Martinez-Climent JA (1).
(1) Division of Hemato-Oncology, Center for Applied Medical Research CIMA, University of Navarra, IDISNA, Pamplona 31008, Spain.
(2) Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB)-CSIC, Madrid 28049, Spain.
(3) Department of Immunology and Biotechnology, Szentágothai Research Center, University of Pécs, Pécs H-7624, Hungary.
(4) Division of Molecular Histopathology, Department of Pathology, Cambridge University, Cambridge CB2 1QP, UK.
(5) MRC Toxicology Unit and Ernest and Helen Scott Haematological Research Institute, Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester LE2 7LX, UK.
(6) Department of Haematology, Royal Bournemouth Hospital, Bournemouth BH7 7DW, UK.
(7) Department of Hematology, Clinica Universidad de Navarra, IDISNA, Pamplona 31008, Spain.
(8) Institute of Human Genetics, Christian-Albrechts-University Kiel &University Hospital Schleswig-Holstein, Campus Kiel, Kiel 24105, Germany.
(9) Bio-informatic Unit, Department of Genomics and Proteomics, Center for Applied Medical Research CIMA, University of Navarra, IDISNA, Pamplona 31008, Spain.
(10) Department of Genetics, School of Medicine, University of Navarra, IDISNA, Pamplona 31008, Spain.
(11) Centre for Translation Cell and Tissue Research, KU Leuven, Leuven 3000, Belgium.
(12) Department of Pathology, Institut Universitaire du Cancer de Toulouse-Oncopole, Labex TOUCAN and CRCT INSERM U1037, Toulouse F-31053, France.
(13) Centro de Biologia Molecular Severo Ochoa, CSIC/Universidad Autonoma, Madrid 28049, Spain.
(14) 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), Salamanca 37007, Spain.
(15) Molecular Genetics Unit, University Hospital Marques de Valdecilla and IFIMAV, Santander 39011, Spain.
(16) Hematology Department, Hospital San Pedro, Logroño, 26006, La Rioja, Spain.
(17) Department of Hematology, Complejo Hospitalario de Navarra, Servicio Navarro de Salud, IDISNA, Pamplona 31008, Spain.
(18) Department of Pathology, Cancer Research Program, Institut Municipal d'Investigacions Mèdiques (IMIM), Hospital del Mar, Barcelona 08003, Spain.
(19) Department of Clinical Hematology, Cancer Research Program, Institut Municipal d'Investigacions Mèdiques (IMIM), Hospital del Mar, Barcelona 08003, Spain.
(20) Department of Hematology, ICO-Hospital Universitari Germans Trias i Pujol, Josep Carreras Leukaemia Research Institute, Universitat Autònoma de Barcelona, Badalona 08916, Spain.
(21) Department of Hematology, IBSAL-University Hospital and IBMCC-CSIC, University of Salamanca, Salamanca 37007, Spain.
(22) Department of Hematology, Hospital Clinico, INCLIVA Biomedical Research Institute, University of Valencia, Valencia 46010, Spain.
(23) Department of Pathology, Hospital Clinico, University of Valencia, Valencia 46010, Spain.
(24) Department of Medicine/Hematology-Oncology, Weill Cornell Medical College, New York, New York 10065, USA.
Magazine: Nature Communications
Date: Jun 14, 2016Cell Therapy Area [SP] Haematology and Hameotherapy
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.
CITATION Nat Commun. 2016 Jun 14;7:11889. doi: 10.1038/ncomms11889
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