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

2016; Nature Portfolio; Volume: 7; Issue: 1 Linguagem: Inglês

10.1038/ncomms11889

2041-1723

Eloy F. Robles, Maria Mena‐Varas, Laura Barrio, Sara V. Merino-Cortés, Péter Balogh, Ming‐Qing Du, Takashi Akasaka, Anton Parker, Sergio Roa, Carlos Panizo, Idoia Martín‐Guerrero, Reiner Siebert, Víctor Segura, Xabier Agirre, Laura Macri-Pellizeri, Beatriz Aldaz, Amaia Vilas‐Zornoza, Shaowei Zhang, Sarah Moody, Marı́a José Calasanz, Thomas Tousseyn, Cyril Broccardo, Pierre Brousset, Elena Campos-Sánchez, César Cobaleda, Isidro Sánchez‐García, José L. Fernández-Luna, Ricardo Garcı́a-Muñoz, Esther Peña, Beatríz Bellosillo, Antonio Salar, Maria João Baptista, Jesús María Hernández‐Rivas, Marcos González, María José Terol, Joan Climent, Antonio Ferŕandez, Xavier Sagaert, Ari Melnick, Felipe Prósper, David Oscier, Yolanda R. Carrasco, Martin J.S. Dyer, José A. Martínez-Climent,

Immunotherapy and Immune Responses

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.