Abstract
Abstract Acute Lymphoblastic Leukemia (ALL) is the most common cancer among children in the US. Approximately 5% of T-cell ALL (T-ALL) cases involve acquired focal chromosomal duplications encompassing a region downstream of the Myc oncogene, characterized as a Notch1-dependent Myc enhancer (N‑Me). The lack of mouse models with such N‑Me duplications has limited our ability to study the molecular mechanisms of the disease. We found that mouse leukemias resulting from conditional aberrant activation of β-catenin with simultaneous ablation of the transcription factor HEB in CD4+CD8+ double positive thymocytes bear N‑Me duplications. The ablation of HEB fundamentally changes the mechanism of leukemogenesis induced by the simple activation of β-catenin, which is characterized by TCRα-Myc/Pvt1 reciprocal translocations. Based on the finding that HEB binds N-Me at a site that overlaps Notch-1 binding and the conserved motifs of other regulators, we propose that HEB has a central regulatory role in the oncogenic process. We hypothesize that HEB binding regulates the access of transcription regulators to N-Me, rationing Myc expression. Loss of HEB in the context of activated β-catenin enables access of these regulators to N-Me, and triggers super-enhancer properties and changes in chromatin conformation, leading to excessive Myc expression and leukemogenesis. Ultimately, the proposed study aspires to determine the role of HEB in the initiation, progression, and treatment of human T-ALL
Published Version
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