Molecular convergence in ex vivo models of Diamond-Blackfan anemia

Kelly A. O'Brien, Jason E. Farrar, Adrianna Vlachos, Stacie M. Anderson, Crystiana A. Tsujiura, Jens Lichtenberg, Lionel Blanc, Eva Atsidaftos, Abdel Elkahloun, Xiuli An, Steven R. Ellis, Jeffrey M. Lipton, David M. Bodine

Research output: Contribution to journalArticlepeer-review

Abstract

Diamond-Blackfan anemia (DBA) is a congenital bone marrow failure syndrome characterized by erythroid hypoplasia, usually without perturbation of other hematopoietic lineages. Approximately 65% of DBA patients with autosomal dominant inheritance have heterozygous mutations or deletions in ribosomal protein (RP) genes while <1% of patients with X-linked inheritance have been identified with mutations in the transcription factor GATA1. Erythroid cells from patients with DBA have not been well characterized, and the mechanisms underlying the erythroid specific effects of either RP or GATA1 associated DBA remain unclear. We have developed an ex vivo culture system to expand peripheral blood CD341 progenitor cells from patients with DBA and differentiate them into erythroid cells. Cells from patients with RP or GATA1 mutations showed decreased proliferation and delayed erythroid differentiation in comparison with controls. RNA transcript analyses of erythroid cells from controls and patients with RP or GATA1 mutations showed distinctive differences, with upregulation of heme biosynthesis genes prominently in RP-mediated DBA and failure to upregulate components of the translational apparatus in GATA1-mediated DBA. Our data showthat dysregulation of translation is a common feature ofDBAcaused by bothRP andGATA1 mutations.

Original languageEnglish (US)
Pages (from-to)3111-3120
Number of pages10
JournalBlood
Volume129
Issue number23
DOIs
StatePublished - Jun 8 2017
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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