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

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, tran...

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Detalles Bibliográficos
Autores: Robles, Eloy F., Mena-Varas, Maria, Barrio, Laura, Merino-Cortes, Sara V., Balogh, Péter, Du, Ming-Qing, Akasaka, Takashi, Parker, Anton, Roa, Sergio, Panizo, Carlos, Martin-Guerrero, Idoia, Siebert, Reiner, Segura, Victor, Agirre, Xabier|||0000-0002-6558-9560, Macri-Pellizeri, Laura, Aldaz, Beatriz, Vilas-Zornoza, Amaia|||0000-0001-6693-0989, Zhang, Shaowei, Moody, Sarah, Calasanz, M.J.|||0000-0002-0374-3008, Tousseyn, Thomas, Broccardo, Cyril, Brousset, Pierre, Campos-Sanchez, Elena, Cobaleda, Cesar|||0000-0003-3807-9204, Sánchez García, Isidro, Fernandez-Luna, Jose Luis, Garcia-Muñoz, Ricardo, Pena, Esther, Bellosillo Paricio, Beatriz|||0000-0002-5335-2726, Salar Silvestre, Antonio|||0000-0002-4652-4825, Baptista, Maria Joao|||0000-0003-3471-2535, Hernández Rivas, Jesús María|||0000-0002-9661-9371, González, Marcos, Terol, Maria Jose|||0000-0002-9467-932X, Climent Bataller, Joan|||0000-0002-8927-6614, Ferrandez, Antonio, Sagaert, Xavier, Melnick, Ari M., Prosper, Felipe|||0000-0001-6115-8790, Oscier, David G., Carrasco, Yolanda R., Dyer, Martin J. S., Martinez-Climent, Jose A.
Tipo de recurso: artículo
Fecha de publicación:2016
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:254163
Acceso en línea:https://ddd.uab.cat/record/254163
https://dx.doi.org/urn:doi:10.1038/ncomms11889
Access Level:acceso abierto
Descripción
Sumario: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. The homeobox NKX2 family of transcriptional factors has been shown to regulate fundamental developmental processes. Here, the authors show that NKX2-3 is a bona fide oncogenic driver in marginal-zone B-cell lymphoma and that it promotes lymphomagenesis by shaping lymphocyte dynamics and promoting BCR signalling.

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