Role of homeobox NKX2-3 protein in marginal-zone B-cell lymphomagenesis using an in vivo mouse model
Palabras clave : 
Biología molecular
Genética molecular
Materias Investigacion::Ciencias de la Salud
Fecha de publicación: 
Fecha de la defensa: 
MENA VARAS, María. “Role of homeobox NKX2-3 protein in marginal-zone B-cell lymphomagenesis using an in vivo mouse model”. Martínez-Clíment, José Ángel (dir.), Robles Cortés, Eloy Francisco (codir.). Tesis doctoral. Universidad de Navarra, Pamplona, 2015
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.

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