A Role for Stroma-Derived Annexin A1 as Mediator in the Control of Genetic Susceptibility to T-Cell Lymphoblastic Malignancies through Prostaglandin E₂ Secretion

¹Departamento de Biología Celular e Inmunología, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid; ²Ciber en Enfermedades Raras y ³Ciber en Epidemiología y Salud Pública, Ministerio de Sanidad y Consumo; ⁴Departamento de Patología Molecular, Unidad de Epigenética del Cáncer, Centro Nacional de Investigaciones Oncológicas; ⁵Area de Epidemiología Ambiental y Cáncer, Centro Nacional de Epidemiología, Instituto de Salud Carlos III, Madrid, Spain; and ⁶Unité de Génétique des Mammifères, Institut Pasteur, Paris, France

^* To whom correspondence should be addressed. E-mail: jfpiqueras{at}cbm.uam.es.

	Abstract

Cancer susceptibility is essentially attributable to multiple low-penetrance genes. Using interspecific consomic and congenic mice between the tumor-resistant SEG/Pas and the tumor-sensitive C57BL/6J strains, a region on chromosome 19 involved in the genetic resistance to -irradiation–induced T-cell lymphomas (Tlyr1) has been identified. Through the development of nonoverlapping subcongenic strains, it has been further shown that Anxa1 may be a candidate resistance gene on the basis of its differential expression in thymus stroma cells after -radiation exposure. In addition, thymus stroma cells of thymic lymphomas exhibited a significant reduction in the expression levels of Anxa1. Interestingly, the activity of Anxa1 relies on prostaglandin E₂ (PGE₂) induction that brings about apoptosis in thymocytes. In fact, in vitro transfection experiments revealed that PGE₂ production was enhanced when HEK 293 cells were transfected with full-length cDNAs of Anxa1, with PGE₂ production in the cells transfected with the allele of the resistant strain (Anxa1^Tyr) being higher than that in cells transfected with the allele of the susceptible strain (Anxa1^Phe). Furthermore, the presence of this compound in the medium induced apoptosis of immature CD4⁺CD8⁺CD3^low cells in a dose-dependent manner. These results improve our knowledge of the molecular mechanisms triggering T-cell lymphoblastic lymphoma development while highlighting the relevance of the stroma in controlling genetic susceptibility and the use of PGE₂ as a new therapeutic approach in T-cell hematologic malignancies. [Cancer Res 2009;69(6):OF1–11]

Key Words: Thymic lymphomas, -irradiation, low-penetrance genes, thymus stroma, Annexin A1