AID is required for germinal center-derived lymphomagenesis.
Most human B cell non-Hodgkin's lymphomas (B-NHLs) derive from germinal centers (GCs), the structure in which B cells undergo somatic hypermutation (SHM) and class switch recombination (CSR) before being selected for high-affinity antibody production. The pathogenesis of B-NHL is associated with distinct genetic lesions, including chromosomal translocations and aberrant SHM, which arise from mistakes occurring during CSR and SHM. A direct link between these DNA remodeling events and GC lymphoma development, however, has not been demonstrated. Here we have crossed three mouse models of B cell lymphoma driven by oncogenes (Myc, Bcl6 and Myc/Bcl6; refs. 5,6) with mice lacking activation-induced cytidine deaminase (AID), the enzyme required for both CSR and SHM. We show that AID deficiency prevents Bcl6-dependent, GC-derived B-NHL, but has no impact on Myc-driven, pre-GC lymphomas. Accordingly, abrogation of AID is associated with the disappearance of CSR- and SHM-mediated structural alterations. These results show that AID is required for GC-derived lymphomagenesis, supporting the notion that errors in AID-mediated antigen-receptor gene modification processes are principal contributors to the pathogenesis of human B-NHL.
Pasqualucci
Laura
L
Institute for Cancer Genetics, the Departments of Pathology and Genetics & Development, and the Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York 10032, USA. lp171@columbia.edu
Bhagat
Govind
G
Jankovic
Mila
M
Compagno
Mara
M
Smith
Paula
P
Muramatsu
Masamichi
M
Honjo
Tasuku
T
Morse
Herbert C
HC
Nussenzweig
Michel C
MC
Dalla-Favera
Riccardo
R
D000818:Animals; D002471:Cell Transformation, Neoplastic; D003564:Cytidine Deaminase / Q000378:metabolism*; D005260:Female; D018858:Germinal Center / Q000378:metabolism* / Q000473:pathology; D016393:Lymphoma, B-Cell / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase