Less than 1 in 2,000 cells in the human body are B-cells.
Once activated, B-cells divide at a faster rate than any other cell type and produce antibodies to neutralize foreign pathogens.
Unlike other cell types, B-cells undergo multiple rounds of somatic gene recombination and hypermutation of immunoglobulin genes to evolve antibodies that bind to antigen with high affinity.
Hence, adaptive immune protection by B-cells comes with an approximately 300-fold increased risk of malignant transformation compared to other cell types.
B-cell leukemia/lymphoma represent the most frequent type of cancer in children (31%) and account for 10% of all cancers in adults.
To prevent the production of harmful autoantibodies and autoimmune disease, autoreactive B-cells and pre-malignant clones are eliminated by a process termed negative selection.
Despite strict and rigorous negative selection, B-cells frequently give rise to autoimmune diseases and B-cell malignancies such as leukemia and lymphoma.
Since humans can live without B-cells for extended periods of time, the Müschen laboratory systematically investigated lineage-specific vulnerabilities that are common in B-cell leukemia/lymphoma but not any other cell type.
Contrary to established dogma, these mechanisms are not only active in preventing autoimmune disease but also represent a novel class of therapeutic oncogenic targets in malignant B-cell tumors.
Over the past five years, the Müschen Laboratory established innovative conceptual frameworks for the understanding of B-cell signaling mechanisms and negative selection, some of which are summarized to the right: