Homeobox NKX2-3 promotes marginal-zone lymphomagenesis by activating B-cell receptor signalling and shaping lymphocyte dynamics
Robles, Eloy F. (Universidad de Navarra)
Mena-Varas, Maria (Universidad de Navarra)
Barrio, Laura (Centro Nacional de Biotecnología (CNB)-CSIC)
Merino-Cortes, Sara V. (Centro Nacional de Biotecnología (CNB)-CSIC)
Balogh, Péter (Department of Immunology and Biotechnology, Szentágothai Research Center, University of Pécs)
Du, Ming-Qing (Division of Molecular Histopathology, Department of Pathology, Cambridge University)
Akasaka, Takashi (MRC Toxicology Unit and Ernest and Helen Scott Haematological Research Institute, Department of Cancer Studies and Molecular Medicine, University of Leicester)
Parker, Anton (Royal Bournemouth General Hospital (Dorset, Regne Unit))
Roa, Sergio (Universidad de Navarra)
Panizo, Carlos (Clínica Universidad de Navarra)
Martin-Guerrero, Idoia (Universitätsklinikum Schleswig-Holstein (Alemanya))
Siebert, Reiner (Universitätsklinikum Schleswig-Holstein (Alemanya))
Segura, Victor (Universidad de Navarra)
Agirre, Xabier (Universidad de Navarra)
Macri-Pellizeri, Laura (Universidad de Navarra)
Aldaz, Beatriz (Universidad de Navarra)
Vilas-Zornoza, Amaia (Universidad de Navarra)
Zhang, Shaowei (Division of Molecular Histopathology, Department of Pathology, Cambridge University)
Moody, Sarah (Division of Molecular Histopathology, Department of Pathology, Cambridge University)
Calasanz, M.J (Universidad de Navarra)
Tousseyn, Thomas (Centre for Translation Cell and Tissue Research, KU Leuven)
Broccardo, Cyril (Department of Pathology, Institut Universitaire du Cancer de Toulouse-Oncopole)
Brousset, Pierre (Department of Pathology, Institut Universitaire du Cancer de Toulouse-Oncopole)
Campos-Sanchez, Elena (Centro de Biología Molecular Severo Ochoa)
Cobaleda, Cesar (Centro de Biología Molecular Severo Ochoa)
Sanchez-Garcia, Isidro (Instituto de Biologia MOolecular y Celular del Cancer de SalamancaA)
Fernandez-Luna, Jose Luis (Hospital Universitario Marqués de Valdecilla (Santander, Cantabria))
Garcia-Muñoz, Ricardo (Hospital San Pedro, Logroño)
Pena, Esther (Complejo Hospitalario de Navarra)
Bellosillo Paricio, Beatriz (Institut Hospital del Mar d'Investigacions Mèdiques)
Salar, Antonio (Institut Hospital del Mar d'Investigacions Mèdiques)
Baptista, Maria Joao (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Hernandez-Rivas, Jesús Maria (Instituto de Investigación Biomédica de Salamanca)
Gonzalez, Marcos (Instituto de Investigación Biomédica de Salamanca)
Terol, Maria Jose (Hospital Clínic Universitari (València))
Climent, Joan (Hospital Clínic Universitari (València))
Ferrandez, Antonio (Hospital Clínic Universitari (València))
Sagaert, Xavier (Centre for Translation Cell and Tissue Research, KU Leuven)
Melnick, Ari M. (Department of Medicine/Hematology-Oncology, Weill Cornell Medical College)
Prosper, Felipe (Universidad de Navarra)
Oscier, David G. (Royal Bournemouth General Hospital (Dorset, Regne Unit))
Carrasco, Yolanda R. (Centro Nacional de Biotecnología (CNB)-CSIC)
Dyer, Martin J. S. (MRC Toxicology Unit and Ernest and Helen Scott Haematological Research Institute, Department of Cancer Studies and Molecular Medicine, University of Leicester)
Martinez-Climent, Jose A. (Universidad de Navarra)

Date:	2016
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. The homeobox NKX2 family of transcriptional factors has been shown to regulate fundamental developmental processes. Here, the authors show that NKX2-3 is a bona fide oncogenic driver in marginal-zone B-cell lymphoma and that it promotes lymphomagenesis by shaping lymphocyte dynamics and promoting BCR signalling.
Grants:	Ministerio de Economía y Competitividad PI12/00202 Ministerio de Economía y Competitividad RD12/0036/0063 Ministerio de Economía y Competitividad RD12/0036/0068 Ministerio de Economía y Competitividad RD12/0036/0022 Ministerio de Economía y Competitividad RD12/0036/0070 Ministerio de Economía y Competitividad RD12/0036/0010 Ministerio de Economía y Competitividad RD12/0036/0044 Ministerio de Economía y Competitividad RD12/0036/0069 Ministerio de Ciencia e Innovación BFU2011-30097 Ministerio de Economía y Competitividad SAF2013-45787-R European Commission 328177 Ministerio de Economía y Competitividad SAF2012-32810 Ministerio de Economía y Competitividad SAF2014-57791-REDC Ministerio de Economía y Competitividad PIE14/00066 Ministerio de Economía y Competitividad PI13/00160 Ministerio de Economía y Competitividad PI14/00025
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Published in:	Nature communications, Vol. 7 (06 2016) , ISSN 2041-1723

DOI: 10.1038/ncomms11889
PMID: 27297662

16 p, 4.3 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP) > Josep Carreras Leukaemia Research Institute
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Articles > Published articles