6533b82efe1ef96bd129324c
RESEARCH PRODUCT
Homeobox NKX2-3 promotes marginal-zone lymphomagenesis by activating B-cell receptor signalling and shaping lymphocyte dynamics
Martin J. S. DyerBeatriz AldazJesús María Hernández-rivasMing-qing DuThomas TousseynElena Campos-sanchezJose A. Martinez-climentXabier AgirreAnton ParkerShaowei ZhangVictor SeguraSara V. Merino-cortesAmaia Vilas-zornozaMaría José CalasanzTakashi AkasakaJose L. Fernandez-lunaCyril BroccardoIdoia Martin-guerreroMaria Joao BaptistaIsidro Sánchez-garcíaMarcos GonzálezXavier SagaertPéter BaloghReiner SiebertAri MelnickSarah MoodyEloy F. RoblesDavid OscierBeatriz BellosilloYolanda R. CarrascoRicardo García-muñozCarlos PanizoFelipe ProsperMaría José TerolLaura Macri-pellizeriCésar CobaledaAntonio SalarEsther PenaAntonio FerrándezLaura BarrioJoan ClimentMaria Mena-varasPierre BroussetSergio Roasubject
0301 basic medicineLymphoid TissueScienceB-cell receptorReceptors Antigen B-CellGeneral Physics and AstronomySykKaplan-Meier EstimateBiologyArticleGeneral Biochemistry Genetics and Molecular BiologyNKX2-303 medical and health sciencesChemokine receptorstomatognathic systemLYNhemic and lymphatic diseasesmedicineAnimalsHumansSyk KinaseLymphocytesPhosphorylationB cellHomeodomain ProteinsMice KnockoutCàncer -- Aspectes molecularsMultidisciplinaryCell adhesion moleculeKinaseGene Expression ProfilingQLymphoma B-Cell Marginal ZoneGeneral Chemistryrespiratory system3. Good healthMice Inbred C57BL030104 developmental biologymedicine.anatomical_structureembryonic structurescardiovascular systemCancer researchCell Adhesion MoleculesProteïnesSignal TransductionTranscription Factorsdescription
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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2016-06-01 | Nature Communications |