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STEM CELL GENETICS AND GENOMICS

Defective Ribosomal Protein Gene Expression Alters Transcription, Translation, Apoptosis, and Oncogenic Pathways in Diamond-Blackfan Anemia

^aDepartment of Pediatric Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA;
^bGenomics Program and Division of Genetics,
^dChildren’s Hospital Informatics Program, and
^hDepartment of Hematology, Children’s Hospital Boston, Boston, Massachusetts, USA;
^cHarvard Medical School, Boston, Massachusetts, USA;
^eDivision of Health Sciences and Technology, Harvard University-Massachusetts Institute of Technology, Boston, Massachusetts, USA;
^fFoundation for Biomedical Research, Academy of Athens, Athens, Greece;
^gDepartment of Hematology/Oncology, University Medical School of Gdansk, Gdansk, Poland

Key Words. Diamond-Blackfan anemia • Bone marrow failure • Global gene expression • Ribosomal protein genes • Apoptosis • Cancer

Correspondence: Hanna Gazda, M.D., Children’s Hospital Boston, Genomics Program and Division of Genetics, 300 Longwood Avenue, Boston, Massachusetts 02115, USA. Telephone: 617-919-4587; Fax: 617-730-0253; e-mail: hanna.gazda{at}childrens.harvard.edu

Received November 9, 2005; accepted for publication May 23, 2006.
First published online in STEM CELLS EXPRESS   June 1, 2006.



Diamond-Blackfan anemia (DBA) is a broad developmental disease characterized by anemia, bone marrow (BM) erythroblastopenia, and an increased incidence of malignancy. Mutations in ribosomal protein gene S19 (RPS19) are found in 25% of DBA patients; however, the role of RPS19 in the pathogenesis of DBA remains unknown. Using global gene expression analysis, we compared highly purified multipotential, erythroid, and myeloid BM progenitors from RPS19 mutated and control individuals. We found several ribosomal protein genes downregulated in all DBA progenitors. Apoptosis genes, such as TNFRSF10B and FAS, transcriptional control genes, including the erythropoietic transcription factor MYB (encoding c-myb), and translational genes were greatly dysregulated, mostly in diseased erythroid cells. Cancer-related genes, including RAS family oncogenes and tumor suppressor genes, were significantly dysregulated in all diseased progenitors. In addition, our results provide evidence that RPS19 mutations lead to codownregulation of multiple ribosomal protein genes, as well as downregulation of genes involved in translation in DBA cells. In conclusion, the altered expression of cancer-related genes suggests a molecular basis for malignancy in DBA. Downregulation of c-myb expression, which causes complete failure of fetal liver erythropoiesis in knockout mice, suggests a link between RPS19 mutations and reduced erythropoiesis in DBA.

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