摘要：

Most B cell non-Hodgkin s lymphomas (B-NHL) derive fromgerminal center (GC) B cells and their pathogenesis is associatedwith the accumulation of distinct genetic lesions, includingchromosomal translocations and a more recently identified mechanismof genomic instability, termed aberrant somatic hypermutation.These alterations are thought to be due to mistakes occurringduring two GC-associated immunoglobulin (Ig) genes remodelingprocesses: class switch recombination (CSR) and somatic hypermutation(SHM). However, this model has never been formally proven. Toconclusively investigate the role of CSR and SHM in the pathogenesisof B-NHL, we examined whether lymphoma development in mice requiresthe function of activation induced cytidine deaminase (AID),a DNA editing enzyme expressed specifically in GC and activatedB cells and essential for both processes. Three transgenic mousemodels were generated by crossing lymphoma-prone mice (MYC,MYC/IµHABCL6 and IµHABCL6) with mice (AID / )that are unable to undergo both SHM and CSR. The MYC mice developa diffusely infiltrating monoclonal proliferation of pre-GCorigin, with unmutated IgV genes and lack of BCL6 expression,and therefore presumably independent from AID-associated DNAremodeling events. Conversely, lymphomas in MYC/IµHABCL6and IµHABCL6 mice recapitulate GC/post GC-derived malignancies,in that the former display somatically mutated IgV genes andupregulation of post-GC markers (CD138) in most of the cases,while the latter develop a splenic lymphoproliferative syndromethat culminates, past 12 months of age, in clonal B cell lymphomaswith DLBCL morphology and somatically mutated IgV genes (~70%of the animals) (Cattoretti et al., Cancer Cell 7:445 455,2005). Mice were monitored for tumor incidence and survival,and a combination of histologic, immunophenotypic and gene expressionprofiling analysis was used for tumor characterization. As expected,no significant differences in event-free survival and lymphomatype were observed between AID-proficient and AID-deficientMYC mice, in agreement with their pre-GC derivation. Conversely,a phenotypic shift of the tumor was observed in MYC/IµHABCL6mice when bred into an AID / background, with >80%of the cases (N=21/26) reverting to a pre-GC phenotype (lossof GC/post GC markers) undistinguishable from that of the MYCand MYC/AID / mice. Gene expression profile analysison representative cases (N=10 MYC/IµHABCL6 and 5 eachfor MYC, MYC/AIDKO, MYC/IµHABCL6/AIDKO) confirmed significantphenotypic similarities between pre-GC derived MYC lymphomasand the MYC/IµHABCL6/AID / lymphomas, whichco-segregated in a separate cluster from MYC/IµHABCL6tumors. Analogously, a significant reduction in DLBCL frequencywas observed in the IµHABCL6/AIDKO cohort as comparedto IµHABCL6 mice (N= 4/19, 21% vs 8/14, 57%; p=0.03).

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