Data from A Role for Stroma-Derived Annexin A1 as Mediator in the Control of Genetic Susceptibility to T-Cell Lymphoblastic Malignancies through Prostaglandin E<sub>2</sub> Secretion

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 γ-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 γ-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):2577–87]