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AID is required for germinal center–derived lymphomagenesis

Abstract

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 production1. 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 SHM2,3,4. 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 SHM7,8. 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.

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Figure 1: AID is dispensable for pre-GC–derived lymphomagenesis.
Figure 2: AID deficiency prevents GC-derived DLBCL development in IμHABCL6 mice.
Figure 3: AID deficiency in λMYC/IμHABCL6 mice prevents the formation of GC-derived lymphomas, but allows pre-GC-type (λMYC-only like) lymphoma development.
Figure 4: AID is required for the accumulation of CSR- and SHM-dependent structural alterations in IμHABCL6 mice.

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Acknowledgements

We thank G. Cattoretti for initial characterization of the mouse models; T. Mo for technical assistance; L. Yang and the Molecular Pathology Facility of the Herbert Irving Comprehensive Cancer Center at Columbia University for histology; V. Miljkovic and J. Pack for assistance with microarray hybridization. This work was supported by National Institutes of Health (NIH) grants (to R.D.-F.), a Leukemia & Lymphoma Society SCOR grant (to R.D.-F.), and in part by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases (to H.C.M.). L.P. is a Julie Gould Scholar.

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Correspondence to Laura Pasqualucci or Riccardo Dalla-Favera.

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Pasqualucci, L., Bhagat, G., Jankovic, M. et al. AID is required for germinal center–derived lymphomagenesis. Nat Genet 40, 108–112 (2008). https://doi.org/10.1038/ng.2007.35

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