AID produces DNA double-strand breaks in non-Ig genes and mature B cell lymphomas with reciprocal chromosome translocations.
Cancer-initiating translocations such as those associated with lymphomas require the formation of paired DNA double-strand breaks (DSBs). Activation-induced cytidine deaminase (AID) produces widespread somatic mutation in mature B cells; however, the extent of "off-target" DSB formation and its role in translocation-associated malignancy is unknown. Here, we show that deregulated expression of AID causes widespread genome instability, which alone is insufficient to induce B cell lymphoma; transformation requires concomitant loss of the tumor suppressor p53. Mature B cell lymphomas arising as a result of deregulated AID expression are phenotypically diverse and harbor clonal reciprocal translocations involving a group of Immunoglobulin (Ig) and non-Ig genes that are direct targets of AID. This group includes miR-142, a previously unknown micro-RNA target that is translocated in human B cell malignancy. We conclude that AID produces DSBs throughout the genome, which can lead to lymphoma-associated chromosome translocations in mature B cells.
Robbiani
Davide F
DF
The Rockefeller University, New York, NY 10065, USA.
Bunting
Samuel
S
Feldhahn
Niklas
N
Bothmer
Anne
A
Camps
Jordi
J
Deroubaix
Stephanie
S
McBride
Kevin M
KM
Klein
Isaac A
IA
Stone
Gary
G
Eisenreich
Thomas R
TR
Ried
Thomas
T
Nussenzweig
André
A
Nussenzweig
Michel C
MC
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000201:enzymology; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D043171:Chromosomal Instability / Q000235:genetics; D033481:Chromosomes, Mammalian / Q000235:genetics*; D003564:Cytidine Deaminase / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D005803:Genes, Immunoglobulin / Q000235:genetics*; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000235:genetics; D007621:Karyotyping; D016393:Lymphoma, B-Cell / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000378:metabolism; D010641:Phenotype; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics; D014178:Translocation, Genetic; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D035683:MicroRNAs; C529102:Mirn142 microRNA, mouse; D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase