PRJNA803273
Nuclear corepressors protect stage-specific integrity during B cell development and safeguard against leukemic transformation
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 at the pre-pro-B cell stage, 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 in proliferating cells. Whole-genome sequencing of Ncor1/2 DKO B cells identified translocations, insertions, and deletions, which were enriched at known RAG1-binding sites. Finally, deletion of Ncor1 alleles in mice facilitated leukemic transformation, while leukemias with less NCOR1 correlated with worse survival. Leukemias with NCOR1 mutations exhibited increased Rag expression that correlated with RAG-linked structural variants. These studies illuminate how the corepressors NCOR1/2 regulate B cell differentiation and provide insights into how NCOR1/2 mutations promote B cell transformation.