Homeobox NKX2-3 promotes marginal-zone lymphomagenesis by activating B-cell receptor signalling and shaping lymphocyte dynamics

Autores: Robles Cortes, Eloy Francisco; Mena Varas, María; Barrio, L.; Merino-Cortés, S. V.; Balogh, P.; Du, M.Q.; Akasaka, T.; Parker, A.; Roa Gómez, Sergio; Panizo Santos, Carlos Manuel; Martín-Guerrero, I.; Siebert, R.; Segura Ruiz, Victor; Aguirre Ena, Xabier; Macri-Peliceri, L.; Aldaz Arrieta, Beatriz; Vilas Zornoza, Amaia; Zhang, S.; Moody, S.; Calasanz Abinzano, María José; Tousseyn, T.; Broccardo, C.; Brousset, P.; Campos-Sánchez, E.; Cobaleda, C.; Sánchez-García, I.; Fernández-Luna, J. L.; García-Muñoz, R.; Pena, E.; Belosillo, B.; Salar, A.; Baptista, M. J.; Hernández-Rivas, J. M.; González, M.; Terol, M. J.; Climent, J.; Ferrandez, A.; Sagaert, X.; Melnick, A. M.; Prosper Cardoso, Felipe; Oscier, D. G.; Carrasco, Y. R.; Dyer, M. J.; Martínez Climent, José Ángel
Título de la revista: NATURE COMMUNICATIONS
ISSN: 2041-1723
Volumen: 7
Páginas: 11889
Fecha de publicación: 2016
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-¿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