Role of homeobox NKX2-3 protein in marginal-zone B-cell lymphomagenesis using an in vivo mouse model
- Autores: María Mena Varas
- Directores de la Tesis: Eloy Francisco Robles Cortés (dir. tes.), José A. Martínez Climent (dir. tes.)
- Lectura: En la Universidad de Navarra ( España ) en 2015
- Idioma: español
- Número de páginas: 166
- Tribunal Calificador de la Tesis: María Dolores Odero de Dios (presid.), Yolanda R. Carrasco (secret.), César Cobaleda Hernández (voc.), Ignacio Pérez Roger (voc.), Manuela Mollejo Villanueva (voc.)
- Materias:
- Enlaces
- Tesis en acceso abierto en: Dadun
- Resumen
NKX2 homeobox family proteins play a role in cancer development. Molecular cloning of a translocation t(10;14)(q24;q32) from a marginal-zone B-cell lymphoma revealed NKX2-3 as an IGH partner gene, leading to increased NKX2-3 expression with respect to B lymphocytes. NKX2-3 overexpression was also detected in tumor cells from a subset of patients with extranodal and splenic marginal-zone lymphomas, but not with other mature B-cell malignancies. While Nkx2-3 deficient mice exhibited atrophic spleens with absence of marginal-zone B cells, transgenic mice with expression of NKX2-3 in B cells showed progressive splenomegaly with marginal-zone expansion, and eventually developed tumors faithfully recapitulating the phenotype, cellular and molecular biology of human marginal-zone lymphomas. Mechanistically, NKX2-3 induced constitutive B-cell receptor (BCR) signaling by phosphorylating Lyn and Syk kinases. These molecules enhanced proliferation and eventually acquiring genomic rearrangements that triggered NF-κB and PI3K-AKT pathways to drive malignant transformation. This study implicates oncogenic NKX2-3 in marginal-zone lymphomagenesis, and provides a valid experimental mouse model for studying the biology and therapy of human lymphoma.
