title: IL-7Rα deficiency in p53null mice exacerbates thymocyte telomere erosion and lymphomagenesis.
abstract: 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.
authors.affiliation: Louisiana State University Health Sciences Center, Gene Therapy Program, New Orleans, LA 70112, USA.
authors.forename: R
authors.initials: R
authors.lastname: Kibe
authors.forename: S
authors.initials: S
authors.lastname: Zhang
authors.forename: D
authors.initials: D
authors.lastname: Guo
authors.forename: L
authors.initials: L
authors.lastname: Marrero
authors.forename: F
authors.initials: F
authors.lastname: Tsien
authors.forename: P
authors.initials: P
authors.lastname: Rodriguez
authors.forename: S
authors.initials: S
authors.lastname: Khan
authors.forename: A
authors.initials: A
authors.lastname: Zieske
authors.forename: J
authors.initials: J
authors.lastname: Huang
authors.forename: W
authors.initials: W
authors.lastname: Li
authors.forename: S K
authors.initials: SK
authors.lastname: Durum
authors.forename: T
authors.initials: T
authors.lastname: Iwakuma
authors.forename: Y
authors.initials: Y
authors.lastname: Cui
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D043171:Chromosomal Instability; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism; D015851:Interleukin-7 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020395:Receptors, Interleukin-7 / Q000235:genetics / Q000378:metabolism*; D000089804:Shelterin Complex; D015398:Signal Transduction; D016615:Telomere / Q000378:metabolism*; D034501:Telomere-Binding Proteins; D060168:Thymocytes / Q000166:cytology / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D015851:Interleukin-7; C507326:POT1 protein, mouse; D020395:Receptors, Interleukin-7; D000089804:Shelterin Complex; D034501:Telomere-Binding Proteins; D016159:Tumor Suppressor Protein p53; C415350:interleukin-7 receptor, alpha chain