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

¹ Dana Farber Cancer Institute, Department of Pediatric Oncology, Boston, Massachusetts; Children's Hospital Boston, Genomics Program and Division of Genetics, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts
² Dana Farber Cancer Institute, Department of Pediatric Oncology, Boston, Massachusetts; Children's Hospital Boston, Children's Hospital Informatics Program, Boston, Massachusetts; Harvard University-Massachusetts Institute of Technology, Division of Health Sciences and Technology, Boston, Massachusetts
³ Children's Hospital Boston, Genomics Program and Division of Genetics, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts; Academy of Athens, Foundation for Biomedical Research, Athens, Greece
⁴ University Medical School of Gdansk, Department of Hematology/Oncology, Gdansk, Poland
⁵ Harvard Medical School, Boston, Massachusetts; Children's Hospital Boston, Children's Hospital Informatics Program, Boston, Massachusetts; Harvard University-Massachusetts Institute of Technology, Division of Health Sciences and Technology, Boston, Massachusetts
⁶ Dana Farber Cancer Institute, Department of Pediatric Oncology, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts; Children's Hospital Boston, Department of Hematology, Boston, Massachusetts
⁷ Children's Hospital Boston, Genomics Program and Division of Genetics, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts

^* To whom correspondence should be addressed. E-mail: hanna-gazda{at}dfci.harvard.edu.

	Abstract

Diamond-Blackfan anemia (DBA) is a broad developmental disease characterized by anemia, bone marrow (BM) erythroblastopenia, and an increased incidence of malignancy. Mutations in a 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 down-regulated in all DBA progenitors. Apoptosis genes like 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 RAB family oncogenes and tumor suppressor genes, were significantly dysregulated in all diseased progenitors. In addition, our results provide evidence that RPS19 mutations lead to co-downregulation of multiple ribosomal protein genes as well as down-regulation 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. Down-regulation 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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