Markus Muschen, MD, PhD

Seminar Title:  Clonal Selection in B Cell Development and Leukemia

Presented by:
Markus Müschen, MD, PhD
HHMI Faculty Scholar & Lee Foundation Professor & Chair,
Department of Systems Biology, Beckman Research Institute;
Associate Director, NCI Comprehensive Cancer Center,
City of Hope National Medical Center, Duarte, CA

Host: Dr. Bridget Wilson

Short Abstract:
Oncogenic drivers in B-lymphoid 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- and T-lymphoid malignancies are unique in that they are also subject to an active negative selection process. B- and T-cells expressing autoreactive antibodies and TCRs, respectively, 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- and T-cells through AIC activation, lymphoid cells fundamentally differ in their signaling requirements from other cell types. Four recent studies from our group showed that despite malignant transformation, B cell- and T cell-lineage leukemia and lymphoma cells are fully sensitive to negative selection and AIC-activation resulting (Chen et al., Nature 2015; Shojaee et al., Cancer Cell 2015; Shojaee et al., Nature Med 2016; Chan et al., Nature 2017). AIC-activation in various lymphoid malignancies is achievable by pharmacological hyperactivation of BCR- and TCR-signaling above a maximum threshold. Unlike other types of cancer, B- and T-cell malignancies are uniquely susceptible to clonal deletion induced by hyperactive signaling from an autoreactive BCR or TCR. Hence, targeted AIC-activation can be leveraged for eradication of drug-resistant leukemia and lymphoma clones.