Two types of BCR interactions are positively selected during leukemia development in the Eμ-TCL1 transgenic mouse model of CLL

Abstract

Key Points• Cell autonomous BCR interactions and interactions with low-affinity autoantigens drive leukemia development in an in vivo model of CLL.• BCR signals induced by binding to external antigen can increase the aggressiveness of CLL.Chronic lymphocytic leukemia (CLL) is a common B-cell malignancy characterized by a highly variable course and outcome. The disease is believed to be driven by B-cell receptor (BCR) signals generated by external antigens and/or cell-autonomous BCR interactions, but direct in vivo evidence for this is still lacking. To further define the role of the BCR pathway in the development and progression of CLL, we evaluated the capacity of different types of antigen/BCR interactions to induce leukemia in the Em-TCL1 transgenic mouse model. We show that cell autonomous signaling capacity is a uniform characteristic of the leukemia-derived BCRs and represents a prerequisite for CLL development. Low-affinity BCR interactions with autoantigens generated during apoptosis are also positively selected, suggesting that they contribute to the pathogenesis of the disease. In contrast, high-affinity BCR interactions are not selected, regardless of antigen form or presentation. We also show that the capacity of the leukemic cells to respond to cognate antigen correlates inversely with time to leukemia development, suggesting that signals induced by external antigen increase the aggressiveness of the disease. Collectively, these findings provide in vivo evidence that the BCR pathway drives the development and can influence the clinical course of CLL. (Blood. 2015;125(10):1578-1588

Integration of innate into adaptive immune responses in ZAP-70–positive chronic lymphocytic leukemia

“…17 Recently, it was elegantly demonstrated in the Em-TCL1 model that both antigendependent and antigen-independent BCR-signals can contribute to disease progression in vivo. 28 Our data now provide evidence that this survival and proliferation signal can autonomously be activated by an innate immune signal. Engagement of TLR9 is able to mount an auto-/paracrine feedback loop based on the activation of the BCR and the subsequent production, secretion, and autorecognition of IgM (Figure 7).…”

Functional Differences between IgM and IgD Signaling in Chronic Lymphocytic Leukemia

“…It is relevant to point out that the Fab stimulating reagents that are used in these and previously published in vitro studies (8–15, 18, 19, 45) differ from the ligands that CLL-BCRs encounter in vivo , and that additional characteristics of the stimulating antigen, including affinity (46, 47) and valency (48, 49), may influence the BCR signaling outcome.…”

Pathogenic role of B-cell receptor signaling and canonical NF-κB activation in mantle cell lymphoma

“…Furthermore, antigen-dependent BCR activation has been shown to accelerate disease progression in mouse lymphoma models and can drive early stages of mucosa-associated lymphoid tissue lymphomas. [40][41][42] Our analysis of primary tumor samples revealed a previously unappreciated importance of BCR and canonical NF-kB signaling in the pathogenesis of MCL, underscoring the value of specifically targeting these pathways. However, depth and durability of response to BTK inhibition differ considerably between lymphoma subtypes.…”