Homeobox NKX2-3 promotes marginal-zone lymphomagenesis by activating B-cell receptor signalling and shaping lymphocyte dynamics
Robles EF (1), Mena-Varas M (1), Barrio L (2), Merino-Cortes SV (2), Balogh P (3), Du MQ (4), Akasaka T (5), Parker A (6), Roa S (1), Panizo C (7), Martin-Guerrero I (8), Siebert R (8), Segura V (9), Agirre X (1), Macri-Pellizeri L (1), Aldaz B (1), Vilas-Zornoza A (1), Zhang S (4), Moody S (4), Calasanz MJ (10), Tousseyn T (11), Broccardo C (12), Brousset P (12), Campos-Sanchez E (13), Cobaleda C (13), Sanchez-Garcia I (14), Fernandez-Luna JL (15), Garcia-Muñoz R (16), Pena E (17), Bellosillo B (18), Salar A (19), Baptista M J (20), Hernandez-Rivas JM (21), Gonzalez M (21), Terol MJ (22), Climent J (22), Ferrandez A (23), Sagaert X (11), Melnick AM (24), Prosper F (1,7), Oscier DG (6), Carrasco YR (2), Dyer MJ (5), Martinez-Climent JA (1).
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.