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. These signaling abnormalities in CLL quantitatively derive from BCR clustering and constitutive signaling with positive feedback reinforcement, as demonstrated through single-cell analysis of phosphor-responses, computational modeling, and super-resolution imaging. Such dysregulated signaling segregates CLL patients by disease severity and clinical presentation. These findings provide a quantitative framework and methodology to assess complex and heterogeneous leukemia pathology and to inform therapeutic strategies in parallel to genomic profiling.