IRB Barcelona BioMed Seminars
by Daniel Herranz, Pharm. D. Ph.D. Assistant Professor of Pharmacology – Cancer Pharmacology Liaison for Center of Outreach and Engagement – Robert Wood Johnson Medical School – Rutgers, Cancer Institute of New Jersey – Rutgers, The State University of New Jersey – USA
T-ALL is a NOTCH1-driven hematological malignancy in which 20% of the patients lose the expression of the tumor suppressor PTEN. Still, not all of these cases can be explained by prototypical mutations/deletions in its coding sequence, which led us to hypothesize there might be additional mechanisms controlling PTEN expression. Indeed, using comprehensive epigenetic profiling, chromosome conformation techniques and novel mouse models, we identified a novel enhancer regulatory region of PTEN (PE) that regulates its expression in T-cells and is recurrently deleted in T-ALL patients, providing a new mechanism for the loss of PTEN expression.
In addition, using a variety of mouse models, epigenetic profiling and unbiased acetyl-proteomics, we have identified a novel therapeutically targetable NOTCH1-SIRT1-KAT7 axis in T-ALL. Sirt1 loss in T-ALL in vivo shows highly antileukemic and synergistic effects with NOTCH1 inhibition. Mechanistically, our data shows that NOTCH1 directly regulates SIRT1 through an enhancer region (N-Se), and SIRT1 itself deacetylates and activates the histone acetyltransferase KAT7. Consequently, hyperacetylated KAT7 upon SIRT1 loss is less active, and this partially mediates the antileukemic effects of SIRT1 loss.