title: Reduced ribosomal protein gene dosage and p53 activation in low-risk myelodysplastic syndrome.
abstract: Reduced gene dosage of ribosomal protein subunits has been implicated in 5q- myelodysplastic syndrome and Diamond Blackfan anemia, but the cellular and pathophysiologic defects associated with these conditions are enigmatic. Using conditional inactivation of the ribosomal protein S6 gene in laboratory mice, we found that reduced ribosomal protein gene dosage recapitulates cardinal features of the 5q- syndrome, including macrocytic anemia, erythroid hypoplasia, and megakaryocytic dysplasia with thrombocytosis, and that p53 plays a critical role in manifestation of these phenotypes. The blood cell abnormalities are accompanied by a reduction in the number of HSCs, a specific defect in late erythrocyte development, and suggest a disease-specific ontogenetic pathway for megakaryocyte development. Further studies of highly purified HSCs from healthy patients and from those with myelodysplastic syndrome link reduced expression of ribosomal protein genes to decreased RBC maturation and suggest an underlying and common pathophysiologic pathway for additional subtypes of myelodysplastic syndrome.
authors.affiliation: Departments of Genetics, Stanford University, Stanford, CA, USA.
authors.forename: Kelly A
authors.initials: KA
authors.lastname: McGowan
authors.forename: Wendy W
authors.initials: WW
authors.lastname: Pang
authors.forename: Rashmi
authors.initials: R
authors.lastname: Bhardwaj
authors.forename: Marcelina G
authors.initials: MG
authors.lastname: Perez
authors.forename: John V
authors.initials: JV
authors.lastname: Pluvinage
authors.forename: Bertil E
authors.initials: BE
authors.lastname: Glader
authors.forename: Reem
authors.initials: R
authors.lastname: Malek
authors.forename: Susan M
authors.initials: SM
authors.lastname: Mendrysa
authors.forename: Irving L
authors.initials: IL
authors.lastname: Weissman
authors.forename: Christopher Y
authors.initials: CY
authors.lastname: Park
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Barsh
mesh_terms: D000818:Animals; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D018628:Gene Dosage / Q000235:genetics / Q000502:physiology; D020022:Genetic Predisposition to Disease; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D009190:Myelodysplastic Syndromes / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D012269:Ribosomal Proteins / Q000235:genetics* / Q000378:metabolism; D012307:Risk Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism* / Q000502:physiology
chemical_list: D012269:Ribosomal Proteins; D016159:Tumor Suppressor Protein p53