Tcl1 Sensitizes B Cells To Transformation By A Pathway Requiring Germinal Center Passage And Induction Of Genomic Instability

4847 Most lymphomas arise by transformation of germinal center (GC) B cells. TCL1, a proto-oncogene first recognized for its role in T cell transformation, also induces GC B cell malignancies when dysregulated in TCL1 transgenic (TCL1) mice. Clonal B cell lymphomas develop from polyclonal populations with latencies of 4 months or more, suggesting that secondary genetic or epigenetic events are required for full transformation. The present study had two goals: to define the GC-specific B cell effects of TCL1 dysregulation that contribute to tumor initiation and to characterize genetic alterations in fully developed tumors that function in disease progression. Here we report that compared to normal cells, B cells from TCL1 mice show enhanced proliferative responses both within and outside the GC. Transgenic B cells are also more resistant to Fas-mediated apoptosis, and express increased levels of activation-induced cytidine deaminase in response to stimulation with IL-4 and LPS or anti-CD40. Remarkably, no B cell lymphomas develop for 20 months when TCL1 mice are crossed onto an OCA-B-deficient background to yield mice incapable of forming GC. Spectral karyotype analysis shows that GC B cell lymphomas from TCL1 mice exhibit recurrent chromosome translocations and trisomy-15, with corresponding MYC overexpression. We conclude that TCL1-expressing B cells primed for transformation must experience the GC environment and, for at least some, develop genome instability to become fully malignant.