Signalling input from divergent pathways subverts Bcell transformation.

Abstract

Malignant transformation typically involves multiple genetic lesions whose combined activity gives rise to cancer1. Our analysis of 1,148 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. Oncogenic lesions in B-ALL frequently mimic cytokine receptor signaling at the pro-B cell stage (through activation of STAT5)2–4 or the pre-B cell receptor in more mature cells (through activation of ERK)5–8. STAT5- and ERK-activating lesions were frequently found but only co-occurred in ~3% of cases (P=2.2E-16). Single-cell mutation and phosphoprotein analyses revealed the segregation of oncogenic STAT5- or ERK-activation to competing clones. STAT5 and ERK engaged opposing biochemical and transcriptional programs orchestrated by MYC and BCL6, respectively. 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.