Homeobox protein NKX2-3 modulates lymphocyte dynamics and promotes B-cell lymphomagenesis

Molecular cloning of a t(10;14)(q24;q32) from a B-cell lymphoma showed a recurrent breakpoint in homeobox NKX2-3 gene, which was highly expressed in comparison to non-expressing mature B lymphocytes. Epigenetically-mediated NKX2-3 over-expression was selectively found in patients with splenic marginal-zone lymphoma, MALT lymphoma and extranodal diffuse large-cell lymphoma. In young mice, restricted expression of NKX2-3 to lymphocytes activated multiple integrins (LFA-1, VLA-4, MAC-1), adhesion molecules (ICAM-1, MadCAM-1, L-selectin) and the chemokine receptor CXCR4 that enhanced their homing and migration to splenic tissues, whereby they were retained, progressively accumulating to form non-clonal tumors. At 18 months, B cells acquired genomic rearrangements and generated clonal B-cell lymphomas mirroring the spectrum of human NKX2-3-expressing tumors. Mouse and human lymphomas displaying NKX2-3 expression shared histopahological, genomic and molecular features, including canonical NF-KB activation. NF-KB inhibition reduced tumorigenecity of NKX2-3-positive lymphomas. Our study reveals that oncogenic NKX2-3 promotes B-cell lymphomagenesis by disturbing lymphocyte dynamics.

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