Nicholas Burwick, MD, and Michael Linenberger, MD
Bellodi C, Kopmar N, Ruggero D. Deregulation of oncogene-induced senescence and p53 translational control in X-linked dyskeratosis congenital. EMBO J 2010;29:1865-1876.
A number of inherited bone marrow failure syndromes (IBMFSs) are associated with altered ribosome biogenesis or function. A common thread among many of these disorders is impaired hematopoiesis and a predisposition to malignancy. Patients with dyskeratosis congenita (DC), a heterogenous disorder caused by defects in components of the telomerase complex, have a 200-fold increased incidence of AML and a thousand-fold increased incidence of squamous cell cancer of the head and neck.1 The X-linked form of DC (X-DC) is caused by mutations in DKC1 that encodes dyskerin, a multifunctional RNA-binding protein involved in both telomerase complex activity and pre-ribosomal RNA modification and processing. The genetically engineered DKC1 hypomorphic mouse (DKC1m) shares many DC phenotypic features, but, notably, half of early generation mice develop tumors of various histologies without associated telomere shortening.2 Impaired dyskerin function alters the translation of mRNAs that utilize an internal ribosome entry site (IRES) element, and IRES-mediated translation is important in cell-cycle control, hypoxia, and apoptosis. Thus, understanding the tumorigenic roles of dysregulated rRNA processing and mRNA translation in X-DC may provide important insights into mechanisms of cancer predisposition in other IBMFSs.
To explore these potential mechanisms, Bellodi and colleagues in the laboratory of Davide Ruggero at the University of California, San Francisco, evaluated IRES-mediated translational responses to oncogene-induced senescence (OIS) and genotoxic stress in the DKC1m mouse model and in primary X-DC cells. They demonstrated that RAS-mediated OIS, which is associated with increased p53 via a switch from cap- to IRES-dependent mRNA translation, was impaired in DKC1m mouse embryonic fibroblasts. DKC1m cells maintained higher proliferative rates and clonogenic potential compared to RAS-transfected wild-type (WT) cells. RAS-induced p53 mRNA levels were similar in DKC1m and WT cells; however, production of p53 protein was blunted in DKC1m cells due to alterations in polyribosomal association with p53 mRNA and depressed IRES-mediated translation. Similarly, reduced p53 translation and cell senescence were observed after exposure of DKC1m cells to etoposide in vitro or to γ-irradiation in vivo. Deregulated p53 translational control was also demonstrated in etoposide-treated human X-DC lymphoblasts and early-passage fibroblasts.
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This important study advances our understanding of stress response and molecular pathogenetic mechanisms of cancer predisposition in X-DC that are independent of telomere-related genomic instability. Recent observations have further implicated reduced dyskerin with impaired p53 activation in breast carcinomas and altered p27 expression in pituitary tumors, suggesting that acquired defects in translational control might promote sporadic malignancies. Hematologists are well versed in the biology of p53, and it is common practice to look for p53 deletions or mutations in certain hematologic malignancies. Deregulated translation of p53, and/or other tumor suppressors, represents a different enemy, but one that might theoretically be targeted by agents that can restore polyribosome association and IRES-mediated translation during genotoxic and oncogenic stress (Figure). The practical take-home message and reminder from this study is that DNA-damaging agents are often poorly tolerated and potentially tumorigenic in individuals with IBMFS and ribosomal dysfunction. Therefore, caution should be exercised when contemplating such drugs for patients with undiagnosed cytopenias.
- Alter BP, Giri N, Savage SA, et al. Malignancies and survival patterns in the National Cancer Institute inherited bone marrow failure syndromes cohort study. Br J Haematol. 2010;150:179-188.
- Ruggero D, Grisendi S, Piazza F, et al. Dyskeratosis congenita and cancer in mice deficient in ribosomal RNA modification. Science. 2003;299:259-262.
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