Integrative functional genomics reveals principles of leukemia core transcriptional circuitry organization

A small set of lineage-restricted transcription factors (TFs), termed core regulatory circuitry (CRC), control cell identity and malignant transformation. Here, we integrated gene dependency, chromatin architecture, TF co-occupancy and RNA expression datasets to characterize CRCs in acute myeloid leukemia (AML). Our approach established hierarchy, modularity, divergence and redundancy as the four basic principles of CRC organization in AML. TF perturbations using genetic knockout and targeted degradation revealed a network dominated by indirect regulation with significantly less direct connections than previously assumed. Super-resolution microscopy visualized dynamic control of mediator recruitment by core TFs and paralog competition in nuclear condensates. Our datasets provide a resource for further inquiries into and therapeutic targeting of aberrant transcriptional circuits in cancer.