Ribosome dysfunction underlies the pathogenesis of many cancers and heritable ribosomopathies. Here, we investigate how mutations in either ribosomal protein large (RPL) or ribosomal protein small (RPS) subunit genes selectively affect erythroid progenitor development and clinical phenotypes in Diamond-Blackfan anemia (DBA), a rare ribosomopathy with limited therapeutic options. Using single-cell assays of patient-derived bone marrow, we delineated two distinct cellular trajectories segregating with ribosomal protein genotypes. Almost complete loss of erythroid specification was observed in RPS-DBA. In contrast, we observed relative preservation of qualitatively abnormal erythroid progenitors and precursors in RPL-DBA. Although both DBA genotypes exhibited a proinflammatory bone marrow milieu, RPS-DBA was characterized by erythroid differentiation arrest, whereas RPL-DBA was characterized by preserved GATA1 expression and activity. Compensatory stress erythropoiesis in RPL-DBA exhibited disordered differentiation underpinned by an altered glucocorticoid molecular signature, including reduced ZFP36L2 expression, leading to milder anemia and improved corticosteroid response. This integrative analysis approach identified distinct pathways of erythroid failure and defined genotype-phenotype correlations in DBA. These findings may help facilitate therapeutic target discovery.

中文翻译：

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人类骨髓祖细胞的单细胞分析揭示了戴蒙德-布莱克凡贫血中红细胞生成失败的机制


核糖体功能障碍是许多癌症和遗传性核糖体病发病机制的基础。在这里，我们研究了核糖体蛋白大（RPL）或核糖体蛋白小（RPS）亚基基因的突变如何选择性地影响钻石-布莱克凡贫血（DBA）的红系祖细胞发育和临床表型，DBA是一种治疗选择有限的罕见核糖体病。通过对患者骨髓进行单细胞分析，我们描绘了两种与核糖体蛋白基因型分离的不同细胞轨迹。在RPS -DBA 中观察到红细胞规格几乎完全丧失。相反，我们观察到RPL -DBA 中质量异常的红系祖细胞和前体细胞的相对保留。尽管两种 DBA 基因型均表现出促炎性骨髓环境，但RPS -DBA 的特点是红系分化停滞，而RPL -DBA 的特点是保留的 GATA1 表达和活性。 RPL -DBA 中的代偿性应激红细胞生成表现出由糖皮质激素分子特征改变（包括ZFP36L2表达减少）导致的分化紊乱，从而导致较轻的贫血和改善的皮质类固醇反应。这种综合分析方法确定了红细胞衰竭的不同途径，并定义了 DBA 中的基因型-表型相关性。这些发现可能有助于促进治疗靶点的发现。