INSERM UMR U1009, Institut Gustave Roussy, Villejuif, France.
Cell Death Dis. 2012 Jul 26;3(7):e356. doi: 10.1038/cddis.2012.88.
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.
Diamond-Blackfan 贫血（DBA）是由于核糖体蛋白（RP）基因突变导致核糖体生物发生异常引起的。为了深入了解 DBA 的发病机制，我们研究了携带 RPL11 和 RPS19 核糖体基因突变的 DBA 患者外周血中的 CD34⁺细胞，并确定了它们在体外进行红细胞分化的能力。RPS19 突变导致祖细胞增殖减少，但终末红细胞分化正常，凋亡很少或没有。这种表型与 p53 途径激活相关的 G₀/G₁ 细胞周期阻滞有关。与此形成鲜明对比的是，RPL11 突变导致祖细胞增殖显著减少，红细胞分化延迟，凋亡明显增加，G₀/G₁ 细胞周期阻滞，p53 激活。用针对 RPS19 或 RPL11 的特异性短发夹（sh）RNA 感染脐带血 CD34⁺细胞，与原代细胞的发现一致，重现了两种截然不同的表型。在两种情况下，p53 通路的表型均被 shRNA p53 敲低逆转。这些结果表明，p53 通路的激活在 DBA 的发病机制中起重要作用，并且可以独立于 RPL11 通路。这些发现为 DBA 的发病机制提供了新的见解。
