B 淋巴细胞生成是由谱系特异性转录因子精心策划的。在 B 细胞祖细胞中，谱系定型由 Pax5 介导，Pax5 在 B 细胞急性淋巴细胞白血病中常见突变。尽管 Pax5 在免疫中发挥重要作用，但调节 Pax5 功能的机制仍然很大程度上未知。在这里，我们发现 NAD 依赖性酶 SIRT7 通过 Pax5 K198 的脱乙酰化来协调 B 细胞发育，从而促进 Pax5 蛋白的稳定性和转录活性。 Pax5K198 去乙酰化和乙酰化模拟物均不能挽救 Pax5-/- pro-B 细胞中的 B 细胞分化，这表明 B 细胞发育需要 Pax5 动态去乙酰化。 Pax5K198 脱乙酰化模拟物恢复了 Pax5-/- pro-B 细胞中的谱系定型和 Sirt7-/- pro-B 细胞中的 B 细胞分化，表明分化与谱系定型脱钩。 SIRT7-Pax5 相互作用在 B 细胞急性淋巴细胞白血病中是保守的，其中 SIRT7 表达与良好预后相关。我们的研究结果揭示了 B 淋巴细胞生成的关键机制，并强调了 Sirtuins 在免疫功能中的相关性。© 2024。作者。

B lymphopoiesis is orchestrated by lineage-specific transcription factors. In B cell progenitors, lineage commitment is mediated by Pax5, which is commonly mutated in B cell acute lymphoblastic leukemia. Despite its essential role in immunity, the mechanisms regulating Pax5 function remain largely unknown. Here, we found that the NAD+-dependent enzyme SIRT7 coordinates B cell development through deacetylation of Pax5 at K198, which promotes Pax5 protein stability and transcriptional activity. Neither Pax5K198 deacetylated nor acetylated mimics rescued B cell differentiation in Pax5-/- pro-B cells, suggesting that B cell development requires Pax5 dynamic deacetylation. The Pax5K198 deacetylation mimic restored lineage commitment in Pax5-/- pro-B cells and B cell differentiation in Sirt7-/- pro-B cells, suggesting the uncoupling of differentiation from lineage commitment. The SIRT7-Pax5 interplay was conserved in B cell acute lymphoblastic leukemia, where SIRT7 expression correlated with good prognosis. Our findings reveal a crucial mechanism for B lymphopoiesis and highlight the relevance of sirtuins in immune function.© 2024. The Author(s).