Molecular regulation of BCL2 to IGH translocation in follicular lymphoma (165.38)

Abstract

Abstract The hallmark of Follicular lymphoma (FL) is the aberrant translocation t(14; 18)(q32; q21) involving the IgH locus on chromosome 14 and BCL2 gene on chromosome 18. Previous analysis showed that approximately 70% of the BCL2/IgH translocations involve the BCL2 major break point region, known as the BCL2-MBR. Accumulating studies suggested that the BCL2-MBR to IgH translocation may be mechanistically similar to IgH DH to JH or VH to DJH recombination. Our analysis of 42 BCL2/IgH break points showed that 60% of them contain clearly identifiable DH genes, suggesting their origin from VH to DJH recombination. Our recent studies showed that the B lineage specific transcriptional factor Pax5 activates IgH VH to DJH recombination through binding to VH gene coding regions and recruiting RAG complexes. Based on this finding, we hypothesize that Pax5 also controls BCL2 to IgH chromosomal translocations. Our initial sequence analyses identified multiple potential Pax5 binding sites within the 150 bp BCL2-MBR. Electrophoresis Mobility Shift Assay (EMSA) demonstrated that Pax5 binds to the individual Pax5 binding sites as well as the full length BCL2-MBR. The BCL2-MBR displays Pax5-dependent enhancer activity when artificially placed in front of a minimal CMV promoter driven luciferase reporter gene. We also found that purified GST-RAG1 and RAG2 core proteins bind to and cleave at the BCL2-MBR. We speculate that Pax5 binding to the BCL2 MBR may enhance BCL2 to IgH recombination.