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

Area of Science:

• Immunology
• Molecular Biology
• Epigenetics

Background:

• Nuclear corepressors NCOR1 and NCOR2 regulate gene expression by interacting with transcription factors.
• These corepressors are implicated in B cell development and chromatin remodeling.

Purpose of the Study:

• To investigate the role of NCOR1 and NCOR2 in B cell differentiation and transformation.
• To elucidate the molecular mechanisms by which NCOR1/2 loss impacts B cell development and leukemogenesis.

Main Methods:

• Mice with Ncor1/2 deletion were used to study B cell differentiation.
• Analysis included pre-BCR signaling, STAT5-dependent transcription, and gene expression profiling.
• Whole-genome sequencing and assessment of human leukemia samples were performed.

Main Results:

• Ncor1/2 deletion impaired B cell differentiation, attenuated pre-BCR signaling, and enhanced STAT5 signaling.
• NCOR1/2-deficient B cells showed derepression of EZH2-repressed genes, including the p53 pathway.
• Loss of NCOR1/2 led to aberrant Rag1/Rag2 expression, increased structural variants, and facilitated leukemic transformation in mice.

Conclusions:

• NCOR1/2 corepressors are critical regulators of B cell differentiation and genomic stability.
• NCOR1/2 mutations contribute to B cell transformation and are associated with worse outcomes in human leukemia.
• Understanding NCOR1/2 function provides insights into B cell development and leukemia pathogenesis.