Super‐Enhancer‐Driven IRF2BP2 is Activated by Master Transcription Factors and Sustains T‐ALL Cell Growth and Survival

Abstract Super enhancers (SEs) are large clusters of transcriptional enhancers driving the expression of genes crucial for defining cell identity. In cancer, tumor‐specific SEs activate key oncogenes, leading to tumorigenesis. Identifying SE‐driven oncogenes in tumors and understanding their functional mechanisms is of significant importance. In this study, a previously unreported SE region is identified in T‐cell acute lymphoblastic leukemia (T‐ALL) patient samples and cell lines. This SE activates the expression of interferon regulatory factor 2 binding protein 2 (IRF2BP2) and is regulated by T‐ALL master transcription factors (TFs) such as ETS transcription factor ERG (ERG), E74 like ETS transcription factor 1 (ELF1), and ETS proto‐oncogene 1, transcription factor (ETS1). Hematopoietic system‐specific IRF2BP2 conditional knockout mice is generated and showed that IRF2BP2 has minimal impact on normal T cell development. However, in vitro and in vivo experiments demonstrated that IRF2BP2 is crucial for T‐ALL cell growth and survival. Loss of IRF2BP2 affects the MYC and E2F pathways in T‐ALL cells. Cleavage under targets and tagmentation (CUT&Tag) assays and immunoprecipitation revealed that IRF2BP2 cooperates with the master TFs of T‐ALL cells, targeting the enhancer of the T‐ALL susceptibility gene recombination activating 1 (RAG1) and modulating its expression. These findings provide new insights into the regulatory network within T‐ALL cells, identifying potential new targets for therapeutic intervention.