title: Molecular convergence in ex vivo models of Diamond-Blackfan anemia.
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 factorGATA1Erythroid cells from patients with DBA have not been well characterized, and the mechanisms underlying the erythroid specific effects of either RP orGATA1associated 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 orGATA1mutations showed decreased proliferation and delayed erythroid differentiation in comparison with controls. RNA transcript analyses of erythroid cells from controls and patients with RP orGATA1mutations showed distinctive differences, with upregulation of heme biosynthesis genes prominently in RP-mediated DBA and failure to upregulate components of the translational apparatus inGATA1-mediated DBA. Our data show that dysregulation of translation is a common feature of DBA caused by both RP andGATA1mutations. This trial was registered at www.clinicaltrials.gov as #NCT00106015.
authors.affiliation: Genetics and Molecular Biology Branch, National Human Genome Research Institute (NHGRI), National Institutes of Health, Bethesda, MD.
authors.forename: Kelly A
authors.initials: KA
authors.lastname: O'Brien
authors.affiliation: Arkansas Children's Research Institute, Little Rock, AR.|Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR.
authors.forename: Jason E
authors.initials: JE
authors.lastname: Farrar
authors.affiliation: 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.
authors.forename: Adrianna
authors.initials: A
authors.lastname: Vlachos
authors.affiliation: Genetics and Molecular Biology Branch, National Human Genome Research Institute (NHGRI), National Institutes of Health, Bethesda, MD.
authors.forename: Stacie M
authors.initials: SM
authors.lastname: Anderson
authors.affiliation: Genetics and Molecular Biology Branch, National Human Genome Research Institute (NHGRI), National Institutes of Health, Bethesda, MD.
authors.forename: Crystiana A
authors.initials: CA
authors.lastname: Tsujiura
authors.affiliation: Genetics and Molecular Biology Branch, National Human Genome Research Institute (NHGRI), National Institutes of Health, Bethesda, MD.
authors.forename: Jens
authors.initials: J
authors.lastname: Lichtenberg
authors.affiliation: 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.
authors.forename: Lionel
authors.initials: L
authors.lastname: Blanc
authors.affiliation: 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.
authors.forename: Eva
authors.initials: E
authors.lastname: Atsidaftos
authors.affiliation: NHGRI Microarray Core, National Institutes of Health, Bethesda, MD.
authors.forename: Abdel
authors.initials: A
authors.lastname: Elkahloun
authors.affiliation: New York Blood Center, New York, NY; and.
authors.forename: Xiuli
authors.initials: X
authors.lastname: An
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Louisville, Louisville, KY.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Ellis
authors.affiliation: 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.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Lipton
authors.affiliation: Genetics and Molecular Biology Branch, National Human Genome Research Institute (NHGRI), National Institutes of Health, Bethesda, MD.
authors.forename: David M
authors.initials: DM
authors.lastname: Bodine
mesh_terms: D000293:Adolescent; D000328:Adult; D029503:Anemia, Diamond-Blackfan / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D041905:Erythroid Cells / Q000378:metabolism / Q000473:pathology; D004920:Erythropoiesis / Q000235:genetics; D005260:Female; D050982:GATA1 Transcription Factor / Q000235:genetics; D005799:Genes, Dominant; D050172:Genes, X-Linked; D006801:Humans; D008297:Male; D008957:Models, Genetic; D009154:Mutation; D012269:Ribosomal Proteins / Q000235:genetics; D059467:Transcriptome; D055815:Young Adult
chemical_list: D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; D012269:Ribosomal Proteins