IL-7Rα deficiency in p53null mice exacerbates thymocyte telomere erosion and lymphomagenesis.

R Kibe, S Zhang, D Guo, L Marrero, F Tsien, P Rodriguez, S Khan, A Zieske, J Huang, W Li, S K Durum, T Iwakuma, Y Cui

Louisiana State University Health Sciences Center, Gene Therapy Program, New Orleans, LA 70112, USA.

Cell death and differentiation 2012 Jul

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Interleukin-7 (IL-7) is an essential T-cell survival cytokine. IL-7 receptor (IL-7Rα) deficiency severely impairs T-cell development due to substantial apoptosis. We hypothesized that IL-7Rα(null)-induced apoptosis is partially contributed by an elevated p53 activity. To investigate the genetic association of IL-7/IL-7Rα signaling with the p53 pathway, we generated IL-7Rα(null)p53(null) (DKO) mice. DKO mice exhibited a marked reduction of apoptosis in developing T cells and an augmented thymic lymphomagenesis with telomere erosions and exacerbated chromosomal anomalies, including chromosome duplications, breaks, and translocations. In particular, Robertsonian translocations, in which telocentric chromosomes fuse at the centromeric region, and a complete loss of telomeres at the fusion site occurred frequently in DKO thymic lymphomas. Cellular and molecular investigations revealed that IL-7/IL-7Rα signaling withdrawal diminished the protein synthesis of protection of telomere 1 (POT1), a subunit of telomere protective complex shelterin, leading to telomere erosion and the activation of the p53 pathway. Blockade of IL-7/IL-7Rα signaling in IL-7-dependent p53(null) cells reduced POT1 expression and caused telomere and chromosome abnormalities similar to those observed in DKO lymphomas. This study underscores a novel function of IL-7/IL-7Rα during T-cell development in regulating telomere integrity via POT1 expression and provides new insights into cytokine-mediated survival signals and T-cell lymphomagenesis.

Citation

R Kibe, S Zhang, D Guo, L Marrero, F Tsien, P Rodriguez, S Khan, A Zieske, J Huang, W Li, S K Durum, T Iwakuma, Y Cui. IL-7Rα deficiency in p53null mice exacerbates thymocyte telomere erosion and lymphomagenesis. Cell death and differentiation. 2012 Jul;19(7):1139-51