Short Telomeres and Ataxia-Telangiectasia Mutated Deficiency Cooperatively Increase Telomere Dysfunction and Suppress Tumorigenesis

To examine the role of ataxia-telanglectasia mutated (Atm) in telomere function, we generated Atm and telomerase null mice (Atm^-/- mTR ^-/- iG6 mice). These mice exhibited increased germ cell death and chromosome fusions compared with either Atm^-/- or mTR^-/- iG6 mice. Furthermore, the Atm^-/- mTR iG6 mice had a delayed onset and reduced incidence of thymic lymphoma compared with Atm ^-/- mice. The tumors in the Atm^-/- mTR^-/- iG6 mice showed Increased apoptosis and anaphase bridges. Finally, lymphomas from Atm^-/- mTR^-/- iG6 mice were derived from CD8 immature, single-positive T cells, whereas Atm^-/- lymphomas were from CD4 ⁺CD8⁺ double-positive T cells. We propose that Atm protects short-telomeres and that Atm deficiency cooperates with short telomeres, leading to increased cell death, decreased tumorigenesis, and increased overall survival.