TitleHomeobox NKX2-3 promotes marginal-zone lymphomagenesis by activating B-cell receptor signalling and shaping lymphocyte dynamics.
Publication TypeJournal Article
Year of Publication2016
AuthorsRobles, Eloy F., Mena-Varas Maria, Barrio Laura, Merino-Cortes Sara V., Balogh Péter, Du Ming-Qing, Akasaka Takashi, Parker Anton, Roa Sergio, Panizo Carlos, Martin-Guerrero Idoia, Siebert Reiner, Segura Victor, Agirre Xabier, Macri-Pellizeri Laura, Aldaz Beatriz, Vilas-Zornoza Amaia, Zhang Shaowei, Moody Sarah, Calasanz Maria Jose, Tousseyn Thomas, Broccardo Cyril, Brousset Pierre, Campos-Sanchez Elena, Cobaleda Cesar, Sanchez-Garcia Isidro, Fernandez-Luna Jose Luis, Garcia-Muñoz Ricardo, Pena Esther, Bellosillo Beatriz, Salar Antonio, Baptista Maria Joao, Hernandez-Rivas Jesús Maria, Gonzalez Marcos, Terol Maria Jose, Climent Joan, Ferrandez Antonio, Sagaert Xavier, Melnick Ari M., Prosper Felipe, Oscier David G., Carrasco Yolanda R., Dyer Martin J. S., and Martinez-Climent Jose A.
JournalNat Commun
Volume7
Pagination11889
Date Published2016 06 14
ISSN2041-1723
KeywordsAnimals, Cell Adhesion Molecules, Gene Expression Profiling, Homeodomain Proteins, Humans, Kaplan-Meier Estimate, Lymphocytes, Lymphoid Tissue, Lymphoma, B-Cell, Marginal Zone, Mice, Inbred C57BL, Mice, Knockout, Phosphorylation, Receptors, Antigen, B-Cell, Signal Transduction, Syk Kinase, Transcription Factors
Abstract

<p>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.</p>

DOI10.1038/ncomms11889
Alternate JournalNat Commun
PubMed ID27297662
PubMed Central IDPMC4911677
Grant List15-1322 / AICR_ / Worldwide Cancer Research / United Kingdom