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 Pax5^K198 deacetylated nor acetylated mimics rescued B cell differentiation in Pax5^−/− pro-B cells, suggesting that B cell development requires Pax5 dynamic deacetylation. The Pax5^K198 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.

B 淋巴细胞生成由 谱系特异性转录因子 协调。在 B 细胞祖细胞中，谱系定型由 Pax5 介导，Pax5 通常在 B 细胞急性淋巴细胞白血病中发生突变。尽管它在免疫中起着重要作用，但调节 Pax5 功能的机制在很大程度上仍然未知。在这里，我们发现 NAD ⁺ 依赖性酶 SIRT7 通过 Pax5 在 K198 位点的脱乙酰化来协调 B 细胞发育，从而促进 Pax5 蛋白的稳定性和转录活性。Pax5^K198 脱乙酰或乙酰化模拟物均未挽救 Pax5 ^−/− pro-B 细胞中的 B 细胞分化，表明 B 细胞发育需要 Pax5 动态脱乙酰化。Pax5^K198 脱乙酰模拟了 Pax5 ^−/− pro-B 细胞中恢复的谱系定型和 Sirt7 ^−/− pro-B 细胞中 B 细胞分化，表明分化与谱系定型的解偶联。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 表达与良好的预后相关。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。