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The transcriptional regulator RBPJ, otherwise known as CSL (“CBF-1, Suppressor of Hairless, Lag-2,” after its mammalian, Drosophila, and Caenorhabditis elegans orthologues) is a highly conserved DNA-binding protein that plays a central role in cell fate decisions in metazoa. RBPJ mediates canonical Notch signaling (1). In the absence of active Notch, RBPJ is thought to be primarily a transcriptional repressor that exists in complexes with corepressors (2). When bound to the active intracellular domain of Notch (NICD), RBPJ recruits a coactivator complex, including a Mastermind homologue (MAML1-3 in mammals), and drives a complex transcriptional program with pervasive phenotypic effects. This program is used during development and adult tissue homeostasis, and is frequently dysregulated in cancer (3, 4). In the hematopoietic system, Notch/RBPJ controls, among other things, the commitment of common lymphoid progenitors to the T-cell lineage and the expansion of marginal-zone B cells (5). Aberrant activation of the Notch–RBPJ transcriptional program in T-lineage cells leads to T-lymphoblastic leukemia (T-LL), and is the most frequent genetic alteration found in this malignancy (6). Epstein–Barr virus (EBV) oncoprotein EBNA2, which is essential for the transforming activity of EBV, has been known for some time to mimic NICD and activate RBPJ (7, 8). EBV-induced immortalization is an important cause of B-cell malignancies such as Burkitt lymphoma and some Hodgkin lymphomas, as well as lymphoproliferative disorders in immune-suppressed patients (9, 10). The structure of DNA-bound RBPJ in complex with NICD and a fragment of MAML1 has been resolved (11, 12). However, the mechanism whereby RBPJ is capable of activating different transcriptional programs in different cells remains unclear. Understanding how RBPJ controls the gene expression programs of T and B cells will give us invaluable insights into physiological cell fate determination and neoplastic transformation. Two reports in PNAS (13, 14) shed …

Transcription factor RBPJ/CSL: A genome-wide look at transcriptional regulation