Using conditional mutagenesis in GC B-cells in the mouse we show that BLIMP1
disruption promotes the development of lymphomas often resembling human ABC-DLBCL. This is in full accord with the results of Mandelbaum et al (Mandelbaum et al., 2010
). The low penetrance, long latency and clonality of DLBCL in these mice suggested that additional oncogenic events are required for the pathogenesis of this disease. A major candidate for one such event is the NF-κB pathway, since the majority of human ABC-DLBCLs display constitutive NF-κB activation, and most lymphomas arising upon conditional BLIMP1
deletion in mice also show activation of this pathway. Indeed, we found that constitutive activation of the canonical NF-κB pathway strongly synergized with loss of BLIMP1
in lymphomagenesis. Thus our work suggests that both NF-κB signaling and the loss of BLIMP1
play causal roles in the pathogenesis of human ABC-DLBCL.
Similar to ABC-DLBCL, genetic alterations leading to constitutive NF-κB activation have been described in multiple myeloma, suggesting a role for this pathway in the pathogenesis of this disease (Annunziata et al., 2007
; Keats et al., 2007
; Staudt, 2010
). Supporting this concept, we found that constitutive activation of NF-κB through the Cγ1-cre transgene promotes plasma cell hyperplasia. If ABC-DLBCLs indeed derive from an activated B-cell at an early stage of plasma cell differentiation (Lenz and Staudt, 2010
), these results in turn indicate that the pathogenesis of this disease necessarily requires interference with terminal B-cell differentiation, as exemplified by BLIMP1
Besides abrogating B-cell terminal differentiation, the loss of BLIMP1
may promote cellular proliferation through derepression of BLIMP1 target genes controlling cell cycle progression (Lin et al., 1997
; Martins and Calame, 2008
). Constitutive activation of the canonical NF-κB pathway, on the other hand, releases B-cells from their dependence of extracellular survival signals, such as BAFF, and although by itself not promoting cell division, enhances the proliferative response of mitogen stimulated B-cells (Sasaki et al., 2006
). Thus, the cooperative effect of BLIMP1
disruption and constitutive NF-κB signaling in the pathogenesis of human ABC-DLBCL likely results from blocking the differentiation of an activated B-cell that displays deregulated proliferative and survival properties.
The increased and abnormally prolonged GC reaction in Cγ1-cre;Blimp1FFeYFPstopFL
mice in conjunction with the presence of somatically mutated Ig gene rearrangements in the lymphomas arising upon BLIMP1
deletion, suggests that the latter likely originate predominantly from either a late or a post-GC B-cell. The situation is less clear in the case of BLIMP1
ablation in combination with activation of the NF-κB pathway, where we did not detect somatic mutations in the majority of the tumors. It is possible that this reflects an inherent feature of our experimental approach, in that NF-κB activation early on in the GC reaction leads to its premature termination ((Bolduc et al., 2010
; Kishi et al., 2010
) and the present work). It may become significant in this situation that the Cγ1-cre
transgene induces Cre-mediated recombination also in a small fraction of IgM expressing non-GC B-cells, whose absolute numbers easily compare to those of GC B-cells (Casola et al., 2006
). Such cells likely include antigen-activated B-cells that have not yet entered the GC reaction (Casola et al., 2006
; Garside et al., 1998
; Toellner et al., 1996
), and to whose proliferative expansion and ultimate transformation Cre-mediated NF-κB activation and loss of BLIMP1
would equally contribute as in the case of B-cells activated in the course of the GC reaction. Indeed, the lymphomas arising in the compound mutants and carrying unmutated Ig gene rearrangements expressed IgM on the cell surface. In this scenario, the present mouse model reproduces the pathogenesis of a B-cell lymphoma originating from the transformation of an activated B-cell, and thus of human ABC-DLBCL. In the latter case, however, the activated cell of origin usually represents a B-cell in which the SHM mechanism is or has been operating, because of its increased risk to accumulate unwanted mutational events (Lenz and Staudt, 2010
). This feature applies less stringently in our system of conditional mutagenesis.
The lymphomas arising upon disruption of BLIMP1 alone and in combination with constitutive NF-κB activation in compound mutant mice are of clonal origin, suggesting that additional oncogenic event/s occurred which led to the outgrowth of a particular B-cell clone. Because of the similarity of these lymphomas with human ABC-DLBCL, the identification of these additional genetic lesions might lead to the discovery of critical players in ABC-DLBCL pathogenesis and open the way to new therapeutic strategies.