The B Cell Antigen Receptor and Overexpression of MYC Can Cooperate in the Genesis of B Cell Lymphomas

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Abstract
A variety of circumstantial evidence from humans has implicated the B cell antigen receptor (BCR) in the genesis of B cell lymphomas. We generated mouse models designed to test this possibility directly, and we found that both the constitutive and antigen-stimulated state of a clonal BCR affected the rate and outcome of lymphomagenesis initiated by the proto-oncogene MYC. The tumors that arose in the presence of constitutive BCR differed from those initiated by MYC alone and resembled chronic B cell lymphocytic leukemia/lymphoma (B-CLL), whereas those that arose in response to antigen stimulation resembled large B-cell lymphomas, particularly Burkitt lymphoma (BL). We linked the genesis of the BL-like tumors to antigen stimulus in three ways. First, in reconstruction experiments, stimulation of B cells by an autoantigen in the presence of overexpressed MYC gave rise to BL-like tumors that were, in turn, dependent on both MYC and the antigen for survival and proliferation. Second, genetic disruption of the pathway that mediates signaling from the BCR promptly killed cells of the BL-like tumors as well as the tumors resembling B-CLL. And third, growth of the murine BL could be inhibited by any of three distinctive immunosuppressants, in accord with the dependence of the tumors on antigen-induced signaling. Together, our results provide direct evidence that antigenic stimulation can participate in lymphomagenesis, point to a potential role for the constitutive BCR as well, and sustain the view that the constitutive BCR gives rise to signals different from those elicited by antigen. The mouse models described here should be useful in exploring further the pathogenesis of lymphomas, and in preclinical testing of new therapeutics. It has long been suspected that the malignant proliferation of B lymphocytes known as lymphomas might represent a perversion of how the cells normally respond to antigen. In particular, the molecular receptor on the surface of the cells that signals the presence of antigen might be abnormally active in lymphomas. We have tested this hypothesis by engineering the genome of mice so that virtually all of the B cells are commandeered by a single version of the surface receptor, then stimulated that receptor with the molecule it is designed to recognize. Our results indicate that both the unstimulated and stimulated states of the receptor can cooperate with an oncogene known as MYC in the genesis of lymphomas. But the two states of the receptor give rise to different forms of lymphoma. In particular, the stimulated form cooperates with MYC to produce a disease that closely resembles Burkitt lymphoma. These results illuminate the mechanisms that are responsible for lymphomas and could inform the development of new strategies to treat the disease.