Dynamics of the B-Cell gene regulatory network in differentiation determine evolutionary trajectories of childhood leukaemogenesis

Abstract

B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) is the most frequent paediatric malignancy. Despite extensive molecular and cellular characterization a mechanistic model of leukaemogenesis has not yet been developed. Here we present a multi-valued logical model of B-cell differentiation, centred on a core pentad of transcription factors whose dysregulation results in the developmental arrest characteristic of BCP-ALL. Whilst B-cell maturation follows a fixed and sequential differentiation process, leukaemic transformation is driven by stochastic genetic insults. Integrating BCR-ABL1 as the initiating event, we model alternative evolutionary trajectories by introducing secondary mutations at different time points within synchronous simulations. We demonstrate that the combination, order and timing of secondary mutations dictate maturation arrest points and fitness, explaining how different patterns of mutations seen in patients may arise and in turn influence disease severity. This platform provides a generalisable framework to model driver mutations in their developmental context to predict evolutionary trajectories in cancer.