Journal
NATURE COMMUNICATIONS
Volume 7, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms11889
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Funding
- Instituto de Salud Carlos III (ISCIII), Spanish Ministry of Economy and Competitiveness [FIS-PI12/00202, RTICC-RD12/0036/0063, RTICC-RD12/0036/0068, RTICC-RD12/0036/0022, RTICC-RD12/0036/0070, RTICC-RD12/0036/0010, RTICC-RD12/0036/0044, RTICC-RD12/0036/0069]
- Worldwide Cancer Research project grant [15-1322]
- MINECO [SAF2013-45787-R]
- Marie Curie Programme [FP7-PIIF-2012-328177]
- French-Spanish CITTIL project
- FIS-ISCIII projects [PI13/00160, PI14/00025]
- Fundacion Inocente Inocente
- Deutsche Krebshilfe, Molecular Mechanisms in Malignant Lymphomas Network Project
- Institut Universitaire de France
- Broad Medical Research Program of The Eli and Edythe Broad Foundation
- Hungarian Scientific Research Fund [OTKA K108429]
- Foundation for Applied Medical Research
- Basque Government
- European Union FEDER program
- [BFU2011-30097]
- [SAF2012-32810]
- [SAF2014-57791-REDC]
- [PIE14/00066]
- [BIO/SA32/14]
- [CSI001U14]
- MRC [MC_U132670597] Funding Source: UKRI
- Medical Research Council [MC_U132670597] Funding Source: researchfish
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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-kappa B 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.
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