title: Primary hematopoietic cells from DBA patients with mutations in RPL11 and RPS19 genes exhibit distinct erythroid phenotype in vitro.
abstract: Diamond-Blackfan anemia (DBA) is caused by aberrant ribosomal biogenesis due to ribosomal protein (RP) gene mutations. To develop mechanistic understanding of DBA pathogenesis, we studied CD34⁺ cells from peripheral blood of DBA patients carrying RPL11 and RPS19 ribosomal gene mutations and determined their ability to undergo erythroid differentiation in vitro. RPS19 mutations induced a decrease in proliferation of progenitor cells, but the terminal erythroid differentiation was normal with little or no apoptosis. This phenotype was related to a G₀/G₁ cell cycle arrest associated with activation of the p53 pathway. In marked contrast, RPL11 mutations led to a dramatic decrease in progenitor cell proliferation and a delayed erythroid differentiation with a marked increase in apoptosis and G₀/G₁ cell cycle arrest with activation of p53. Infection of cord blood CD34⁺ cells with specific short hairpin (sh) RNAs against RPS19 or RPL11 recapitulated the two distinct phenotypes in concordance with findings from primary cells. In both cases, the phenotype has been reverted by shRNA p53 knockdown. These results show that p53 pathway activation has an important role in pathogenesis of DBA and can be independent of the RPL11 pathway. These findings shed new insights into the pathogenesis of DBA.
authors: INSERM UMR U1009, Institut Gustave Roussy, Villejuif, France.
authors: H
authors: H
authors: Moniz
authors: M
authors: M
authors: Gastou
authors: T
authors: T
authors: Leblanc
authors: C
authors: C
authors: Hurtaud
authors: A
authors: A
authors: Crétien
authors: Y
authors: Y
authors: Lécluse
authors: H
authors: H
authors: Raslova
authors: J
authors: J
authors: Larghero
authors: L
authors: L
authors: Croisille
authors: M
authors: M
authors: Faubladier
authors: O
authors: O
authors: Bluteau
authors: L
authors: L
authors: Lordier
authors: G
authors: G
authors: Tchernia
authors: W
authors: W
authors: Vainchenker
authors: N
authors: N
authors: Mohandas
authors: L
authors: L
authors: Da Costa
mesh_terms: D029503:Anemia, Diamond-Blackfan / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018952:Antigens, CD34 / Q000378:metabolism; D017209:Apoptosis; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D002675:Child, Preschool; D041905:Erythroid Cells / Q000166:cytology / Q000378:metabolism*; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D010641:Phenotype; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D012269:Ribosomal Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D018952:Antigens, CD34; D034741:RNA, Small Interfering; D012269:Ribosomal Proteins; D016159:Tumor Suppressor Protein p53; C027624:ribosomal protein L11; C040343:ribosomal protein S19