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

Abstract 3453

Aberrant expression of TAL1 is one of the most frequent abnormalities in T-cell acute lymphoblastic leukemia (T-ALL), yet little is known about the transcriptional network controlled by this oncogenic transcription factor, posing a major obstacle to understanding T-ALL pathogenesis. Here we identify the core transcriptional regulatory circuit controlled by TAL1 and its regulatory partners HEB, E2A, GATA3 and RUNX1 in T-ALL cells. We determined direct transcriptional targets of TAL1 and its regulatory partners by ChIP-seq analysis, and found that TAL1 binds to the majority of HEB- and E2A-enriched regions and that these commonly bound regions are frequently overlapping with the GATA3- and RUNX1-enriched regions. We found that TAL1 forms an interconnected auto-regulatory loop with its partners, which likely contribute to the sustained upregulation of its direct target genes. TAL1 core regulatory circuit activates genes involved in T-cell development and hematopoesis. Microarray gene expression analysis revealed that TAL1 and GATA3 predominantly act as positive regulators of the expression of their direct target genes in T-ALL. Importantly, we found the MYB oncogenic transcription factor is directly activated by the TAL1 complex and positively regulates many of the same target genes, thus forming a feed-forward positive regulatory loop that further promotes the TAL1-regulated oncogenic program. Moreover, we found that a specific subset of TAL1 target genes are oppositely regulated by TAL1 and its obligate partner proteins E2A and HEB, uncovering a leukemogenic pattern that previously emerged from studies in murine models. These findings underscore the importance of TAL1 as a critical regulator of an aberrant gene expression program in T-ALL, and indicate how these networks maintain the malignant state in thymocytes.