Core Transcriptional Regulatory Circuit Controlled by the TAL1 Complex in Human T Cell Acute Lymphoblastic Leukemia

SummaryThe oncogenic transcription factor TAL1/SCL is aberrantly expressed in over 40% of cases of human T cell acute lymphoblastic leukemia (T-ALL), emphasizing its importance in the molecular pathogenesis of T-ALL. Here we identify the core transcriptional regulatory circuit controlled by TAL1 and its regulatory partners HEB, E2A, LMO1/2, GATA3, and RUNX1. We show that TAL1 forms a positive interconnected autoregulatory loop with GATA3 and RUNX1 and that the TAL1 complex directly activates the MYB oncogene, forming a positive feed-forward regulatory loop that reinforces and stabilizes the TAL1-regulated oncogenic program. One of the critical downstream targets in this circuitry is the TRIB2 gene, which is oppositely regulated by TAL1 and E2A/HEB and is essential for the survival of T-ALL cells.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (177 K)Download as PowerPoint slideHighlights► TAL1, GATA3, and RUNX1 form a positive interconnected autoregulatory loop ► TAL1 core regulatory circuit controls genes involved in T cell homeostasis ► The TAL1 complex recruits MYB in a positive feed-forward regulatory loop ► TRIB2 is oppositely regulated by TAL1 and E-proteins and is crucial for cell survival