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Blood. 2017 Jun 8;129(23):3111-3120. doi: 10.1182/blood-2017-01-760462. Epub 2017 Apr 4.

Molecular convergence in ex vivo models of Diamond-Blackfan anemia.

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Genetics and Molecular Biology Branch, National Human Genome Research Institute (NHGRI), National Institutes of Health, Bethesda, MD.
Arkansas Children's Research Institute, Little Rock, AR.
Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR.
Feinstein Institute for Medical Research, Manhasset, NY.
Division of Hematology/Oncology and Stem Cell Transplantation, Cohen Children's Medical Center, New Hyde Park, NY.
Hofstra Northwell School of Medicine, Hempstead, NY.
NHGRI Microarray Core, National Institutes of Health, Bethesda, MD.
New York Blood Center, New York, NY; and.
Department of Biochemistry and Molecular Genetics, University of Louisville, Louisville, KY.


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 CD34+ 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 show that dysregulation of translation is a common feature of DBA caused by both RP and GATA1 mutations. This trial was registered at as #NCT00106015.

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