Session: 622. Lymphoma Biology—Non-Genetic Studies: Poster I
Hematology Disease Topics & Pathways:
Biological, Diseases, Leukemia, Therapies, Biological Processes, B-Cell Lymphoma, immunotherapy, Lymphoid Malignancies, signal transduction
Results: Oncogenic drivers in B- cell malignancies function as mimics of B-cell receptor (BCR) signaling. Oncogenic activation of BCR-signaling represents the functional equivalent of positive selection during normal lymphocyte development. Addiction to survival and proliferation signals (or the equivalent of positive selection) is a common feature in many types of cancer. However, B-cell malignancies are unique in that they are also subject to an active negative selection process. B-cells expressing autoreactive BCRs or antibodies can cause systemic autoimmunity. As a safeguard against autoimmune diseases, lymphocyte development evolved autoimmunity checkpoints (AIC) to eliminate autoreactive clones. Owing to negative selection of autoreactive B-cells through AIC activation, lymphoid cells fundamentally differ in their signaling requirements from other cell types. Recent studies from our group showed that despite malignant transformation, B-cell leukemia and lymphoma cells are fully sensitive to negative selection and AIC-activation resulting (Chen et al., Nature 2015; Shojaee et al., Nature Med 2016; Chan et al., Nature 2017; Xiao et al., Cell 2018).
AIC-activation in various lymphoid malignancies is achievable by pharmacological hyperactivation of BCR-signaling above a maximum threshold (see Schematic below). Unlike other types of cancer, B-cell malignancies are uniquely susceptible to clonal deletion induced by hyperactive signaling from an autoreactive BCR. Hence, targeted AIC-activation can be leveraged for eradication of drug-resistant leukemia and lymphoma clones. Here, we propose a novel strategy to overcome drug-resistance in B-lymphoid malignancies based on targeted activation of autoimmunity checkpoints (AIC) for removal of autoreactive B-lymphocytes.
We have recently discovered that targeted hyperactivation of SYK, PI3K and ERK in B cell malignancies represents the functional equivalent of an autoimmunity checkpoint (AIC) for elimination of autoreactive clones among normal B cells. B cell tumors are uniquely vulnerable to AIC activation, suggesting that targeted activation of this checkpoint represents a novel strategy to induce cell death in otherwise drug-resistant B cell malignancies.
Conclusion: Normal B-cells are positively selected for BCR signaling of intermediate strength (moderate activation of SYK, PI3K and ERK). In the absence of a functional BCR, SYK, PI3K and ERK activity fall below a minimum threshold, resulting in death by neglect. Hyperactivation above maximum thresholds (e.g. autoreactive BCR) triggers negative selection and cell death via AIC-activation. Targeted therapy of cancer typically focuses on agents that suppress oncogenic signaling below a minimum threshold. Our results support a novel strategy to overcome drug-resistance in B-cell malignancies based on targeted activation of autoimmunity checkpoints (AIC) for removal of autoreactive cells.
Disclosures: No relevant conflicts of interest to declare.
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