Defective ribosomal protein gene expression alters transcription, translation, apoptosis, and oncogenic pathways in Diamond-Blackfan anemia

Hanna T. Gazda, Alvin T. Kho, Despina Sanoudou, Jan M. Zaucha, Isaac S. Kohane, Colin A. Sieff, Alan H. Beggs

Research output: Contribution to journalArticle

65 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)2034-2044
Number of pages11
JournalStem Cells
Volume24
Issue number9
DOIs
Publication statusPublished - 5 Oct 2006
Externally publishedYes

Fingerprint

Diamond-Blackfan Anemia
Ribosomal Proteins
Apoptosis
Gene Expression
Genes
Down-Regulation
Erythropoiesis
Neoplasm Genes
Mutation
myb Genes
Bone Marrow
Erythroid Cells
Liver Failure
Tumor Suppressor Genes
Oncogenes
Knockout Mice
Anemia
Neoplasms
Transcription Factors

Keywords

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

ASJC Scopus subject areas

  • Cell Biology

Cite this

Gazda, H. T., Kho, A. T., Sanoudou, D., Zaucha, J. M., Kohane, I. S., Sieff, C. A., & Beggs, A. H. (2006). Defective ribosomal protein gene expression alters transcription, translation, apoptosis, and oncogenic pathways in Diamond-Blackfan anemia. Stem Cells, 24(9), 2034-2044. https://doi.org/10.1634/stemcells.2005-0554

Defective ribosomal protein gene expression alters transcription, translation, apoptosis, and oncogenic pathways in Diamond-Blackfan anemia. / Gazda, Hanna T.; Kho, Alvin T.; Sanoudou, Despina; Zaucha, Jan M.; Kohane, Isaac S.; Sieff, Colin A.; Beggs, Alan H.

In: Stem Cells, Vol. 24, No. 9, 05.10.2006, p. 2034-2044.

Research output: Contribution to journalArticle

Gazda, Hanna T. ; Kho, Alvin T. ; Sanoudou, Despina ; Zaucha, Jan M. ; Kohane, Isaac S. ; Sieff, Colin A. ; Beggs, Alan H. / Defective ribosomal protein gene expression alters transcription, translation, apoptosis, and oncogenic pathways in Diamond-Blackfan anemia. In: Stem Cells. 2006 ; Vol. 24, No. 9. pp. 2034-2044.
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