Mechanisms promoting translocations in editing and switching peripheral B cells

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• Variable, diversity, and joining (V(D)J) recombination and class switch recombination (CSR) are crucial for immunoglobulin gene assembly and function.
• Both V(D)J and CSR rely on DNA double-strand breaks (DSBs) repaired by non-homologous end-joining (NHEJ).
• Errors in these processes can lead to chromosomal translocations, implicated in B cell lymphomas.

Purpose of the Study:

• To investigate the controversial occurrence of V(D)J recombination in peripheral B cells.
• To explore the potential collaboration between V(D)J recombination and CSR in generating translocations.
• To identify mechanistic factors contributing to recurrent translocations in tumors.

Main Methods:

• Analysis of activated, NHEJ-deficient splenic B cells.
• Detection of V(D)J recombination-associated breaks at the lambda IgL locus (Igl).
• Assessment of CSR-associated IgH breaks and translocation formation.
• Investigation of Igh-Igl and Igh-c-myc co-localization.
• Introduction of c-myc DSBs to study translocation promotion.

Main Results:

• NHEJ-deficient splenic B cells accumulate V(D)J-associated breaks at Igl and CSR-associated breaks at Igh.
• Igl and Igh breaks frequently join to form translocations, often associated with Igh-Igl co-localization.
• Igh and c-myc co-localization is observed, and c-myc DSBs robustly promote Igh-c-myc translocations.
• Evidence suggests peripheral B cells attempt secondary V(D)J recombination.

Conclusions:

• Peripheral B cells can undergo secondary V(D)J recombination.
• Mechanistic factors contribute to the formation of recurrent translocations in tumors.
• The study clarifies the role of V(D)J recombination in peripheral B cells and its link to oncogenic translocations.