TY - JOUR
T1 - Homeobox NKX2-3 promotes marginal-zone lymphomagenesis by activating B-cell receptor signalling and shaping lymphocyte dynamics
AU - Robles, Eloy F.
AU - Mena-Varas, Maria
AU - Barrio, Laura
AU - Merino-Cortes, Sara V.
AU - Balogh, Péter
AU - Du, Ming Qing
AU - Akasaka, Takashi
AU - Parker, Anton
AU - Roa, Sergio
AU - Panizo, Carlos
AU - Martin-Guerrero, Idoia
AU - Siebert, Reiner
AU - Segura, Victor
AU - Agirre, Xabier
AU - Macri-Pellizeri, Laura
AU - Aldaz, Beatriz
AU - Vilas-Zornoza, Amaia
AU - Zhang, Shaowei
AU - Moody, Sarah
AU - Calasanz, Maria Jose
AU - Tousseyn, Thomas
AU - Broccardo, Cyril
AU - Brousset, Pierre
AU - Campos-Sanchez, Elena
AU - Cobaleda, Cesar
AU - Sanchez-Garcia, Isidro
AU - Fernandez-Luna, Jose Luis
AU - Garcia-Muñoz, Ricardo
AU - Pena, Esther
AU - Bellosillo, Beatriz
AU - Salar, Antonio
AU - Baptista, Maria Joao
AU - Hernandez-Rivas, Jesús Maria
AU - Gonzalez, Marcos
AU - Terol, Maria Jose
AU - Climent, Joan
AU - Ferrandez, Antonio
AU - Sagaert, Xavier
AU - Melnick, Ari M.
AU - Prosper, Felipe
AU - Oscier, David G.
AU - Carrasco, Yolanda R.
AU - Dyer, Martin J.S.
AU - Martinez-Climent, Jose A.
PY - 2016/6/14
Y1 - 2016/6/14
N2 - 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.
AB - 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.
U2 - 10.1038/ncomms11889
DO - 10.1038/ncomms11889
M3 - Article
VL - 7
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
M1 - 11889
ER -