Official websites use. Share sensitive information only on official, secure websites. Hurtz, S. Hong and Z. Malignant transformation typically involves multiple genetic lesions whose combined activity gives rise to cancer 1.
Our analysis of 1, patient-derived B-cell leukemia B-ALL samples revealed that individual mutations did not promote leukemogenesis unless they converged on one single oncogenic pathway characteristic for the differentiation stage of transformed B cells.
Mutations not aligned with the central oncogenic driver activated divergent pathways and subverted transformation. Genetic reactivation of the divergent suppressed pathway came at the expense of the principal oncogenic driver and reversed transformation.
Conversely, deletion of divergent pathway components accelerated leukemogenesis. Thus, persistence of divergent signaling pathways represents a powerful barrier to transformation while convergence on one principal driver defines a central event in leukemia-initiation.
Pharmacological reactivation of suppressed divergent circuits strongly synergized with inhibition of the principal oncogenic driver. Hence, reactivation of divergent pathways can be leveraged as a previously unrecognized strategy to deepen treatment responses. During early B-cell development, cytokine receptors e. Malignant transformation typically involves cooperation of multiple genetic lesions 1 , suggesting that adding oncogenic drivers to existing mutations would accelerate tumor progression.
