文章：

PICH缺陷限制MYC诱导的B细胞淋巴瘤进展

PICH deficiency limits the progression of MYC-induced B-cell lymphoma

原文发布日期：2024-01-23

DOI: 10.1038/s41408-024-00979-y

类型: Article

开放获取: 是

英文摘要：

Plk1-interacting checkpoint helicase (PICH) is a DNA translocase involved in resolving ultrafine anaphase DNA bridges and, therefore, is important to safeguard chromosome segregation and stability. PICH is overexpressed in various human cancers, particularly in lymphomas such as Burkitt lymphoma, which is caused by MYC translocations. To investigate the relevance of PICH in cancer development and progression, we have combined novel PICH-deficient mouse models with the Eμ-Myc transgenic mouse model, which recapitulates B-cell lymphoma development. We have observed that PICH deficiency delays the onset of MYC-induced lymphomas in Pich heterozygous females. Moreover, using a Pich conditional knockout mouse model, we have found that Pich deletion in adult mice improves the survival of Eμ-Myc transgenic mice. Notably, we show that Pich deletion in healthy adult mice is well tolerated, supporting PICH as a suitable target for anticancer therapies. Finally, we have corroborated these findings in two human Burkitt lymphoma cell lines and we have found that the death of cancer cells was accompanied by chromosomal instability. Based on these findings, we propose PICH as a potential therapeutic target for Burkitt lymphoma and for other cancers where PICH is overexpressed.
 

摘要翻译： 

Plk1相互作用检查点解旋酶（PICH）是一种DNA易位酶，参与解析超细后期DNA桥，因而对保障染色体分离与稳定性至关重要。PICH在多种人类癌症中过度表达，尤其在伯基特淋巴瘤等由MYC易位引发的淋巴瘤中。为探究PICH在癌症发生发展中的作用，我们将新型PICH缺陷小鼠模型与重现B细胞淋巴瘤发展的Eμ-Myc转基因小鼠模型相结合。研究发现，在Pich杂合子雌性小鼠中，PICH缺陷可延缓MYC诱导的淋巴瘤发生。此外，通过条件性敲除小鼠模型发现，成年小鼠中敲除Pich能提升Eμ-Myc转基因小鼠的生存率。值得注意的是，健康成年小鼠中敲除Pich具有良好的耐受性，这证实PICH可作为抗癌治疗的合适靶点。最后，我们在两种人类伯基特淋巴瘤细胞系中验证了上述发现，并观察到癌细胞死亡伴随染色体不稳定性。基于这些结果，我们认为PICH可作为伯基特淋巴瘤及其他PICH过表达癌症的潜在治疗靶点。

原文链接：

PICH deficiency limits the progression of MYC-induced B-cell lymphoma