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Mechanisms of B-cell dynamics and oncogenic signaling
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 below:
Energy abundance sets thresholds for negative B-cell selection
Regulation of energy-abundance is the central determinant of negative B-cell selection: Hyperactivation of kinases downstream of an autoreactive B-cell receptor induces ATP depletion and energy stress (Chen et al., 2015; Shojaee et al., 2016).
B-cells not only have the smallest cytoplasmic volume but also fewer mitochondria than any other cell type. The new paradigm on ‘metabolic gatekeeper functions’ is based on B-lymphoid transcription factors repressing or limiting glucose-uptake and energy-supply to set low thresholds for negative selection of autoreactive and premalignant B-cells (Chan et al., 2017; Pan et al., 2021).
Diverting glucose flux
Glucose carbon-flux during B-cell transformation is diverted in a way that leaves transformed B-cells uniquely vulnerable to inhibition of PP2A, an enzyme that coordinates glycolytic flux with antioxidant protection (Xiao et al., 2018).
Diversity of signaling input and malignant transformation
Only mutations that converge on one central pathway promote leukemia-progression. Genetic reactivation of divergent (suppressed) pathways engage conflicting biochemical and transcriptional programs and subvert leukemia development. Pharmacological pathway-reactivation to create a diverse signaling environment can be leveraged as a new therapeutic to prevent leukemia progression (Chan et al, 2020).
A new feedback loop of PI3K-amplification
The endosomal protein IFITM3 was found to play a role as a central scaffold for lipid-raft assembly and surface-expression of rafts-associated receptors during B-cell activation. Recruitment of IFITM3 is critical for the initiation of PI3K-signaling, antibody affinity maturation and oncogenic B-cell transformation (Lee et al., 2020).
Goldilocks principle of B-cell selection
Thresholds of B-cell selection are based on signaling strength of the B-cell receptor (BCR). While B-cells with a non-functional BCR lack critical BCR-signals for survival, autoreactive B-cells elicit overwhelming strong BCR-signals. According to a Goldilocks principle of B-cell selection, only clones with intermediate BCR-signaling strength (“just right”) are positively selected to survive and proliferate. Targeted hyperactivation of BCR-downstream kinases mimics excessive signaling strength from autoreactive BCRs, thus triggering negative selection. Traditional cancer therapy is focused on kinase inhibitors to suppress oncogenic signaling so kinase hyperactivation is a novel approach for targeted therapy in B-cell malignancies (Müschen 2018; Müschen 2019).