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

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.

Elucidation of tonic and activated B-cell receptor signaling in Burkitt’s lymphoma provides insights into regulation of cell survival

“…Despite the importance of BCR signaling in the pathogenesis of BL, drug target identification in BL-specific BCR signaling networks is hampered by incomplete understanding of the full spectrum of BCR-mediated events (4,11). We therefore aimed at comprehensively characterizing BCR signaling in BL by pursuing a quantitative phosphoproteomic approach ( Fig.…”

Oncogenic Mechanisms in Burkitt Lymphoma

“…This observation suggests that BL may rely on BCR signaling. Moreover, transgenic mouse models suggested a role of BCR signaling in MYCdriven lymphomagenesis (Refaeli et al 2008). Crossing antigen-specific BCR transgenic mice with MYC transgenic mice affects the rate and outcome of lymphomagenesis initiated by MYC.…”

The tyrosine kinase Syk regulates the survival of chronic lymphocytic leukemia B cells through PKCδ and proteasome-dependent regulation of Mcl-1 expression

“…However, studies now indicate that abnormal expression of Syk and ZAP-70 may also contribute to hematologic malignancies (Goodman et al, 2001;Crespo et al, 2006;Wossning et al, 2006;Feldman et al, 2008). Other studies indicate that constitutively activated Syk may be a central determinant of B-CLL (Gobessi et al, 2009) and B-cell lymphoma survival (Leseux et al, 2006;Chen et al, 2008;Refaeli et al, 2008). Altogether those studies suggest that Syk is a major component of neoplastic B-cell survival.…”