IgH partner breakpoint sequences provide evidence that AID initiates t(11;14) and t(8;14) chromosomal breaks in mantle cell and Burkitt lymphomas.
Previous studies have implicated activation-induced cytidine deaminase (AID) in B-cell translocations but have failed to identify any association between their chromosomal breakpoints and known AID target sequences. Analysis of 56 unclustered IgH-CCND1 translocations in mantle cell lymphoma across the ~ 344-kb bcl-1 breakpoint locus demonstrates that half of the CCND1 breaks are near CpG dinucleotides. Most of these CpG breaks are at CGC motifs, and half of the remaining breaks are near WGCW, both known AID targets. These findings provide the strongest evidence to date that AID initiates chromosomal breaks in translocations that occur in human bone marrow B-cell progenitors. We also identify WGCW breaks at the MYC locus in Burkitt lymphoma translocations and murine IgH-MYC translocations, both of which arise in mature germinal center B cells. Finally, we propose a developmental model to explain the transition from CpG breaks in early human B-cell progenitors to WGCW breaks in later stage B cells.
Department of Laboratory Medicine, University of Washington, Seattle, WA 98195, USA. greisman@uw.edu
Harvey A
HA
Greisman
Zhengfei
Z
Lu
Albert G
AG
Tsai
Timothy C
TC
Greiner
Hye Son
HS
Yi
Michael R
MR
Lieber
D000818:Animals; D002051:Burkitt Lymphoma / Q000235:genetics*; D019457:Chromosome Breakage; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics*; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics*; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics*; D055028:Comparative Genomic Hybridization; D018899:CpG Islands; D019938:Cyclin D1 / Q000235:genetics; D003564:Cytidine Deaminase / Q000235:genetics*; D016259:Genes, myc; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D020522:Lymphoma, Mantle-Cell / Q000235:genetics*; D051379:Mice; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D014178:Translocation, Genetic / Q000235:genetics*; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
C530104:CCND1 protein, human; C529133:IGH-CCND1 fusion protein, human; D007143:Immunoglobulin Heavy Chains; D015514:Oncogene Proteins, Fusion; D019938:Cyclin D1; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase