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

Abstract

<div>Abstract<p>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 (<i>Tlyr1</i>) has been identified. Through the development of nonoverlapping subcongenic strains, it has been further shown that <i>Anxa1</i> 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 <i>Anxa1</i>. Interestingly, the activity of <i>Anxa1</i> relies on prostaglandin E<sub>2</sub> (PGE<sub>2</sub>) induction that brings about apoptosis in thymocytes. In fact, <i>in vitro</i> transfection experiments revealed that PGE<sub>2</sub> production was enhanced when HEK 293 cells were transfected with full-length cDNAs of <i>Anxa1</i>, with PGE<sub>2</sub> production in the cells transfected with the allele of the resistant strain (<i>Anxa1</i><sup>Tyr</sup>) being higher than that in cells transfected with the allele of the susceptible strain (<i>Anxa1</i><sup>Phe</sup>). Furthermore, the presence of this compound in the medium induced apoptosis of immature CD4<sup>+</sup>CD8<sup>+</sup>CD3<sup>low</sup> 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 PGE<sub>2</sub> as a new therapeutic approach in T-cell hematologic malignancies. [Cancer Res 2009;69(6):2577–87]</p></div>