美国明尼苏达大学Michael A. Farrar研究组发现核辅抑制因子NCOR1/NCOR2调节B细胞发育，维持基因组完整性并防止转化。这一研究成果于2022年10月31日发表在国际顶尖学术期刊《自然—免疫学》上。

他们证明了Ncor1/2的缺失通过重组障碍限制B细胞的分化，减弱了pre-BCR信号，增强了STAT5依赖的转录。此外，NCOR1/2缺陷的B细胞表现出EZH2抑制基因模块的去抑制，包括p53通路。这些改变导致了Rag1和Rag2的异常表达和可及性。对Ncor1/2 DKO B细胞的全基因组测序发现，具有隐性重组信号序列的结构变异数量增加。

最后，小鼠中Ncor1等位基因的缺失促进了白血病的转化，而Ncor1缺少导致的人类白血病与较差的生存率相关。人类白血病中的NCOR1/2突变与RAG表达的增加和结构变异的数量相关。这些研究阐明了辅抑制因子NCOR1/2如何调节B细胞分化，并为NCOR1/2突变如何促进B细胞转化提供了见解。

研究人员表示，核辅抑制因子NCOR1和NCOR2与参与B细胞发育的转录因子相互作用，并可能将这些因子与染色质结构和基因表达的改变联系起来。

附：英文原文

Title: Nuclear corepressors NCOR1/NCOR2 regulate B cell development, maintain genomic integrity and prevent transformation

Author: Lee, Robin D., Knutson, Todd P., Munro, Sarah A., Miller, Jeffrey T., Heltemes-Harris, Lynn M., Mullighan, Charles G., Jepsen, Kristen, Farrar, Michael A.

Issue&Volume: 2022-10-31

Abstract: The nuclear corepressors NCOR1 and NCOR2 interact with transcription factors involved in B cell development and potentially link these factors to alterations in chromatin structure and gene expression. Herein, we demonstrate that Ncor1/2 deletion limits B cell differentiation via impaired recombination, attenuates pre-BCR signaling and enhances STAT5-dependent transcription. Furthermore, NCOR1/2-deficient B cells exhibited derepression of EZH2-repressed gene modules, including the p53 pathway. These alterations resulted in aberrant Rag1 and Rag2 expression and accessibility. Whole-genome sequencing of Ncor1/2 DKO B cells identified increased number of structural variants with cryptic recombination signal sequences. Finally, deletion of Ncor1 alleles in mice facilitated leukemic transformation, whereas human leukemias with less NCOR1 correlated with worse survival. NCOR1/2 mutations in human leukemia correlated with increased RAG expression and number of structural variants. These studies illuminate how the corepressors NCOR1/2 regulate B cell differentiation and provide insights into how NCOR1/2 mutations may promote B cell transformation.

DOI: 10.1038/s41590-022-01343-7

Source: https://www.nature.com/articles/s41590-022-01343-7