Role of homeobox NKX2-3 protein in marginal-zone B-cell lymphomagenesis using an in vivo mouse model

  1. Mena Varas, María
Dirigida por:
  1. Eloy Francisco Robles Cortés Director/a
  2. José A. Martínez Climent Director

Universidad de defensa: Universidad de Navarra

Fecha de defensa: 21 de septiembre de 2015

Tribunal:
  1. María Dolores Odero de Dios Presidenta
  2. Yolanda R. Carrasco Secretario/a
  3. Manuela Mollejo Villanueva Vocal
  4. César Cobaleda Hernández Vocal
  5. Ignacio Pérez Roger Vocal
Departamento:
  1. (FM) Unidad de Medicina Traslacional

Tipo: Tesis

Teseo: 120148 DIALNET lock_openDadun editor

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.