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BCL6 breaks occur at different AID sequence motifs in Ig-BCL6 and non-Ig-BCL6 rearrangements

Zhengfei Lu1, Albert G Tsai, Takashi Akasaka

  • 1Norris Comprehensive Cancer Center, Department of Pathology, Biochemistry, and Molecular Biology, University of Southern California, Los Angeles, CA, USA.

Blood
|March 12, 2013
PubMed

Insights

BCL6 translocations in B-cell lymphomas often involve immunoglobulin genes and occur during class-switch recombination. Breakpoints suggest activation-induced deaminase activity, with distinct patterns for immunoglobulin versus non-immunoglobulin partners.

Area of Science:

  • Genetics
  • Molecular Biology
  • Cancer Research

Background:

  • BCL6 translocations are prevalent in B-cell lymphomas.
  • These translocations frequently involve immunoglobulin heavy chain (IgH) switch regions.
  • This suggests a role for class-switch recombination in their formation.

Purpose of the Study:

  • To analyze the breakpoint distribution and sequence motifs in BCL6 translocations.
  • To investigate the mechanisms underlying BCL6 rearrangements in B-cell lymphomas.
  • To differentiate between immunoglobulin (Ig) and non-immunoglobulin (non-Ig) translocation partners.

Main Methods:

  • Analysis of 120 BCL6 translocation breakpoints within a specific segment of BCL6 intron 1.
  • Identification of breakpoint junctions with IgH, Ig light chains, and non-Ig partners.
  • Sequence analysis to identify DNA motifs, including activation-induced cytosine deaminase (AID) hotspots and CpG sites.

Main Results:

  • A significant portion of BCL6 breaks occurred in Ig regions (62% IgH, 10% Ig light chains).
  • BCL6 breaks in Ig-BCL6 translocations favored AID hotspots (WGCW, WRC).
  • Non-Ig rearrangements showed breaks at both AID hotspots and CpG/CGC sites, distinct from previously observed CpG breaks in other B-cell stages.

Conclusions:

  • BCL6 translocations in germinal center B-cells are likely initiated by AID.
  • The differential use of AID hotspots and CpG sites suggests distinct mechanisms for Ig-BCL6 versus non-Ig-BCL6 rearrangements.
  • These findings provide insights into the molecular pathogenesis of BCL6-driven lymphomas.

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