Constitutive Activation of BCR Explains Dysfunctional Signaling in Chronic Lymphocytic Leukemia

Abstract

In cancer biology, functional interpretation of genomic alterations is critical to achieve the promise of genomic profiling in the clinic. For Chronic Lymphocytic Leukemia (CLL), a heterogeneous disease of B-lymphocytes maturing under constitutive B-cell receptor (BCR) stimulation, the functional role of diverse clonal mutations remains largely unknown. Here, we demonstrate that alterations in BCR signaling dynamics underlie the progression of B-cells toward malignancy. We reveal emergent dynamic features, namely bimodality, hypersensitivity, and hysteresis, in the BCR signaling pathway of primary CLL B-cells. Such signaling abnormalities in CLL quantitatively derive from BCR clustering and constitutive signaling with positive feedback reinforcement, as demonstrated through single-cell analysis of signaling motifs, computational modeling, and super-resolution imaging. Such dysregulated signaling segregates CLL patients by disease severity and clinical presentation. These findings provide a novel quantitative framework and methodology to assess complex and heterogeneous leukemia pathology and to inform therapeutic strategies in parallel to genomic profiling.