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Blood, 1 September 2008, Vol. 112, No. 5, pp. 1552-1553. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Shimamura, A. Search for Related Content PubMed Articles by Shimamura, A. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  RED CELLS Comment on Farrar et al, page 1582 Diamond-Blackfan anemia: a new facet Akiko Shimamura FRED HUTCHINSON CANCER RESEARCH CENTER In this issue of Blood, Farrar and colleagues report the first mutations affecting the 60S large ribosomal subunit in DBA, providing further support for the concept of a a central role for ribosome biogenesis in marrow failure. Mutations in an increasing number of genes encoding 40S small ribosomal subunit proteins have been associated with marrow failure and leukemogenesis. RPS19 mutations have been identified in 25% of patients with Diamond-Blackfan anemia(DBA),1 with resulting impairment of 18S rRNA processing and 40S ribosomal subunit formation.2–4 The subsequent association between DBA and mutations in 2 additional 40S ribosomal subunit genes, RPS245 and RPS17,6 further supported the notion that the small ribosomal subunit plays an important role in DBA. Acquired defects in another 40S ribosomal protein gene, RPS14, were recently identified in patients with the 5q- myelodysplastic syndrome,7,8 suggesting that 40S ribosomal abnormalities constitute a general pathway underlying hematopoietic disorders. Nonetheless, the caveat remained that additional extra-ribosomal functions have been described for many ribosomal proteins and the possibility that these 40S subunit proteins might serve additional cellular functions could not be excluded. Hence, the relative contribution of ribosomal dysfunction to marrow disorders was unclear. Now, Farrar et al have mapped a fourth DBA gene encoding a 60S large ribosomal subunit protein, RPL35A, in 5 out of a cohort of 150 patients with DBA (3.3%). They also confirmed that RPL35A sequence changes were not found in 180 healthy controls. The authors went further to test the functional consequences of RPL35A loss. They demonstrated that reduction of RPL35A expression by shRNAs resulted in decreased proliferation and viability of human hematopoietic cell lines. Impaired ribosomal 60S subunit biogenesis was observed following RPL35A knock-down and in DBA patient samples. These comprehensive findings together with prior studies of RPS19 convincingly demonstrate that disruption of either 40S or 60S ribosomal subunit biogenesis is associated with DBA. This new evidence lends considerable support for the role of ribosomal disruption as a fundamental factor in DBA. Since mutations in the 4 known DBA genes are identified in only one-third of DBA patients, it is possible that additional 40S and 60S ribosomal protein genes might also contribute to DBA. In support of this hypothesis, Farrar et al also identified aberrant processing of the 60S subunit rRNAs in DBA patients for whom RPL35A mutations were not identified. Since the majority of DBA patients lack known mutations, it would be of considerable interest to determine whether impaired ribosome biogenesis constitutes a characteristic feature of all DBA patients. If true, functional assays for DBA-specific abnormalities in ribosome biogenesis might be useful diagnostically. The molecular mechanisms whereby disruption of ribosome biogenesis results in marrow failure and malignant transformation remain to be defined. Several hypotheses have been proposed. One possibility is that incomplete ribosome assembly directly contributes to these processes, for example, through the activation of cellular stress responses or through direct cellular toxicity. Another possibility is that disruption of ribosome biogenesis exerts downstream effects on protein translation that, in turn, are responsible for the DBA phenotype. Impairment of ribosome biogenesis has also been described in other phenotypically diverse marrow failure syndromes, such as Shwachman-Diamond syndrome, X-linked dyskeratosis congenita, and cartilage-hair hypoplasia. Elucidating the molecular similarities and differences between these ribosomal disorders stand to advance our understanding of how inherited and acquired abnormalities in ribosomal pathways contribute to hematopoietic failure and malignancy. Footnotes Conflict-of-interest disclosure: The author declares no competing financial interests. REFERENCES Draptchinskaia N, Gustavsson P, Andersson B, et al. The gene encoding ribosomal protein S19 is mutated in Diamond-Blackfan anaemia. Nat Genet. 1999;21:169–175.[CrossRef][Medline] [Order article via Infotrieve] Choesmel V, Bacqueville D, Rouquette J, et al. Impaired ribosome biogenesis in Diamond-Blackfan anemia. Blood. 2007;109:1275–1283.[Abstract/Free Full Text] Flygare J, Aspesi A, Bailey JC, et al. Human RPS19, the gene mutated in Diamond-Blackfan anemia, encodes a ribosomal protein required for the maturation of 40S ribosomal subunits. Blood. 2007;109:980–986.[Abstract/Free Full Text] Idol RA, Robledo S, Du HY, et al. Cells depleted for RPS19, a protein associated with Diamond Blackfan Anemia, show defects in 18S ribosomal RNA synthesis and small ribosomal subunit production. Blood Cells Mol Dis. 2007;39:35–43.[CrossRef][Medline] [Order article via Infotrieve] Gazda HT, Grabowska A, Merida-Long LB, et al. Ribosomal protein S24 gene is mutated in Diamond-Blackfan anemia. Am J Hum Genet. 2006;79:1110–1118.[CrossRef][Medline] [Order article via Infotrieve] Cmejla R, Cmejlova J, Handrkova H, et al. Ribosomal protein S17 gene (RPS17) is mutated in Diamond-Blackfan anemia. Hum Mutat. 2007;28:1178–1182.[CrossRef][Medline] [Order article via Infotrieve] Ebert BL, Pretz J, Bosco J, et al. Identification of RPS14 as a 5q- syndrome gene by RNA interference screen. Nature. 2008;451:335–339.[CrossRef][Medline] [Order article via Infotrieve] Pellagatti A, Hellstrom-Lindberg E, Giagounidis A, et al. Haploinsufficiency of RPS14 in 5q- syndrome is associated with deregulation of ribosomal- and translation-related genes. Br J Haematol. 2008;142:57–64.[CrossRef][Medline] [Order article via Infotrieve] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Abnormalities of the large ribosomal subunit protein, Rpl35a, in Diamond-Blackfan anemia Jason E. Farrar, Michelle Nater, Emi Caywood, Michael A. McDevitt, Jeanne Kowalski, Clifford M. Takemoto, C. Conover Talbot, Jr, Paul Meltzer, Diane Esposito, Alan H. Beggs, Hal E. Schneider, Agnieszka Grabowska, Sarah E. Ball, Edyta Niewiadomska, Colin A. Sieff, Adrianna Vlachos, Eva Atsidaftos, Steven R. Ellis, Jeffrey M. Lipton, Hanna T. Gazda, and Robert J. Arceci Blood 2008 112: 1582-1592. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Shimamura, A. Search for Related Content PubMed Articles by Shimamura, A. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?

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