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 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 (Anxa1Tyr) being higher than that in cells transfected with the allele of the susceptible strain (Anxa1Phe). Furthermore, the presence of this compound in the medium induced apoptosis of immature CD4+CD8+CD3low 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]