英国利兹大学Joan Boyes课题组开发出从V(D)J重组中切除的DNA环促进白血病复发。这一研究成果发表在2025年8月6日出版的国际学术期刊《自然》上。

在这里，该课题组研究人员表明ESCs在许多细胞世代中复制和持续存在，并与环状染色体外DNA具有许多共同特性。B细胞前体急性淋巴细胞白血病诊断时ESC拷贝数增加与随后的复发高度相关。通过利用在每个ESC生成时形成的匹配重组足迹，研究团队测量了ESC的持久性和复制，并发现后来复发的患者中ESC复制增加。这种增加的复制是由细胞内在因素控制的，并与DNA复制和修复相关基因的表达增加相对应。与高水平的ESC在疾病进展中的作用一致，由V(D)J重组酶- ESC复合物引导的典型突变数量在后来复发的患者诊断时显着增加。这种与复发相关的基因突变的数量在诊断和复发之间增加，并且与高ESC拷贝数的细胞克隆扩增相对应。这些数据表明，V(D)J重组的副产物，当丰度增加时，可能与V(D)J重组酶相关，以改变不良的疾病结果。

据了解，染色体外DNA扩增与癌症预后不良有关。在V(D)J重组过程中，作为抗原受体重排的副产物产生了大量切除的信号圈（ESCs）。然而，目前的观点认为，胚胎干细胞是在细胞分裂过程中逐渐丢失的。

附：英文原文

Title: Excised DNA circles from V(D)J recombination promote relapsed leukaemia

Author: Gao, Zeqian, Scott, James N. F., Edwards, Matthew P., Casey, Dylan, Wang, Xiaoling, Gillen, Andrew D., Ryan, Sarra, Russell, Lisa J., Moorman, Anthony V., de Tute, Ruth, Cargo, Catherine, Ford, Anthony M., Westhead, David R., Boyes, Joan

Issue&Volume: 2025-08-06

Abstract: Extrachromosomal DNA amplification is associated with poor cancer prognoses1. Large numbers of excised signal circles (ESCs) are produced as by-products of antigen receptor rearrangement during V(D)J recombination2,3. However, current dogma states that ESCs are progressively lost through cell division4. Here we show that ESCs replicate and persist through many cell generations and share many properties in common with circular extrachromosomal DNAs. Increased ESC copy numbers at diagnosis of B cell precursor acute lymphoblastic leukaemia were highly correlated with subsequent relapse. By taking advantage of the matching recombination footprint that is formed upon the generation of each ESC, we measured ESC persistence and replication and found increased ESC replication in patients who later relapsed. This increased replication is controlled by cell-intrinsic factors and corresponds to increased expression of DNA replication- and repair-associated genes. Consistent with high ESC levels having a role in disease progression, the number of mutations typical of those caused by the V(D)J recombinase–ESC complex was significantly increased at diagnosis in patients who later relapsed. The number of such mutations in genes associated with relapse increased between diagnosis and relapse, and corresponded to clonal expansion of cells with high ESC copy numbers. These data demonstrate that the by-product of V(D)J recombination, when increased in abundance, potently associates with the V(D)J recombinase to cause adverse disease outcomes.

DOI: 10.1038/s41586-025-09372-6

Source: https://www.nature.com/articles/s41586-025-09372-6