The maintenance of B cell identity requires active transcriptional control that enforces a B cell-specific program and suppresses alternative lineage genes. Accordingly, disrupting the B cell identity regulatory network compromises B cell function and induces cell fate plasticity by allowing derepression of alternative lineage-specific transcriptional programs. Although the B lineage is incredibly resistant to most differentiating factors, loss of just a single B lineage-specific transcription factor or the forced expression of individual non-B cell lineage transcription factors can radically disrupt B cell maintenance and allow dedifferentiation or transdifferentiation into entirely distinct lineages. B lymphocytes thereby offer an insightful and useful case study of how a specific cell lineage can maintain a stable identity throughout life and how perturbations of a single master regulator can induce cellular plasticity. In this article, we review the regulatory mechanisms that safeguard B cell identity, and we discuss how dysregulation of the B cell maintenance program can drive malignant transformation and enable therapeutic resistance.
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