Super-enhancer reprogramming drives a B cell-epithelial transition and high-risk leukemia. Mus musculus

IKAROS is required for the differentiation of highly proliferative pre-B cell precursors and loss-of-IKAROS function indicates poor prognosis in precursor B-cell acute lymphoblastic leukemia (B-ALL). Here we show that IKAROS regulates this developmental stage by positive and negative regulation of super-enhancers with distinct lineage affiliation. IKAROS together with B cell master regulators, such as PAX5, EBF1 and IRF4, defines super-enhancers at pre-B cell differentiation genes and is required for a highly permissive chromatin environment, a function that cannot be compensated for by the other transcription factors. IKAROS, is also highly enriched at inactive enhancers of genes normally expressed in stem-epithelial cells. Upon IKAROS loss, expression of pre-B cell differentiation genes is attenuated, while a group of extra-lineage transcription factors, directly repressed by IKAROS, and dependent on EBF1 re-localization at their enhancers, are induced. LHX2, LMO2 and TEAD-YAP1 together with other native B cell transcription regulators induce a feed-forward transcriptional loop based on their direct cooperation within a de novo super-enhancer network normally kept separate by IKAROS. Induction of de novo super-enhancers antagonizes Polycomb repression and superimposes aberrant stem-epithelial cell properties in a B cell precursor. This dual mechanism of IKAROS regulation promotes differentiation while safeguarding against a hybrid stem-epithelial-B cell phenotype that underlies high-risk B-ALL. Overall design: 35 CHiPseq samples including input controls from WT and IKDN stromal adherent preB cells