Chromatin Biology Laboratory, Josep Carreras Leukemia Research Institute, Badalona, Spain.
Cancer Epigenetics Laboratory, Josep Carreras Leukemia Research Institute, Badalona, Spain.
Nat Immunol. 2024 Dec;25(12):2308-2319. doi: 10.1038/s41590-024-01995-7. Epub 2024 Oct 18.
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 deacetylated nor acetylated mimics rescued B cell differentiation in Pax5 pro-B cells, suggesting that B cell development requires Pax5 dynamic deacetylation. The Pax5 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 细胞发生是由谱系特异性转录因子精心调控的。在 B 细胞前体细胞中，谱系决定由 Pax5 介导，其在 B 细胞急性淋巴细胞白血病中普遍发生突变。尽管 Pax5 在免疫中具有重要作用，但调节其功能的机制在很大程度上仍不清楚。在这里，我们发现 NAD 依赖性酶 SIRT7 通过 Pax5 的 K198 去乙酰化来协调 B 细胞发育，从而促进 Pax5 蛋白稳定性和转录活性。Pax5 去乙酰化或乙酰化模拟物都不能挽救 Pax5 pro-B 细胞中的 B 细胞分化，这表明 B 细胞发育需要 Pax5 的动态去乙酰化。Pax5 去乙酰化模拟物恢复了 Pax5 pro-B 细胞中的谱系决定，并在 Sirt7 pro-B 细胞中恢复了 B 细胞分化，表明分化与谱系决定的解耦。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 的表达与良好的预后相关。我们的发现揭示了 B 细胞发生的一个关键机制，并强调了 Sirtuins 在免疫功能中的相关性。
