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

Eloy F. Robles, Maria Mena-Varas, Laura Barrio, Sara V. Merino-Cortes, Péter Balogh, Ming Qing Du, Takashi Akasaka, Anton Parker, Sergio Roa, Carlos Panizo, Idoia Martin-Guerrero, Reiner Siebert, Victor Segura, Xabier Agirre, Laura Macri-Pellizeri, Beatriz Aldaz, Amaia Vilas-Zornoza, Shaowei Zhang, Sarah Moody, Maria Jose CalasanzThomas Tousseyn, Cyril Broccardo, Pierre Brousset, Elena Campos-Sanchez, Cesar Cobaleda, Isidro Sanchez-Garcia, Jose Luis Fernandez-Luna, Ricardo Garcia-Muñoz, Esther Pena, Beatriz Bellosillo, Antonio Salar, Maria Joao Baptista, Jesús Maria Hernandez-Rivas, Marcos Gonzalez, Maria Jose Terol, Joan Climent, Antonio Ferrandez, Xavier Sagaert, Ari M. Melnick, Felipe Prosper, David G. Oscier, Yolanda R. Carrasco, Martin J.S. Dyer, Jose A. Martinez-Climent

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22 Citations (Scopus)

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.
Original languageEnglish
Article number11889
JournalNature Communications
Volume7
DOIs
Publication statusPublished - 14 Jun 2016

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