Pharmacological inhibition of the transcription factor PU.1 as a novel treatment for acute myeloid leukemia
Albert Einstein College of Medicine
Project Term: July 1, 2018 - June 30, 2021
Transcription factors are components of a cell which control our genetic information and are known to have altered function in diseases such as Acute Myeloid Leukemia (AML). I am investigating how we can better understand and use novel transcription factor drugs as therapy for AML. This involves using CLICK-chemistry drug localization studies and creating transcription factor occupancy maps of the genome. Overall, my work will help to understand the inner workings of transcription factors in disease and provide a new therapeutic option for the treatment of AML.
Acute Myeloid Leukemia (AML) is the most common adult leukemia, characterized by excessive proliferation of abnormal immature white blood cells, and continues to have a dismal survival rate amongst all subtypes of leukemia (<40% five-year overall survival rate). AML development occurs through an acquisition of mutations over time, including mutations in transcription factor genes. Transcription factors are components of a cell which control the expression of genetic information by binding to regions of the DNA. Their expression and/or function is often changed in cancer, and this leads to incorrect gene expression. PU.1 is a transcription factor that has changed expression or function in more than half of all AML patients, demonstrating that PU.1 is an attractive therapeutic target. Drugs inhibiting transcription factors have not yielded much success in the past. However, our lab has discovered a small molecule compound that can inhibit PU.1 function to the point that AML cells die. This inhibitor blocks PU.1 function by blocking its binding to DNA. Since this drug is not ready for clinical use, my project seeks to identify more PU.1 inhibitors that may be better candidates for clinical development. In addition, I seek to better understand how PU.1 inhibitors functions so that more potent PU.1 inhibitors can be produced. My colleagues and I are determining how PU.1 inhibitor compounds kill AML cells, including leukemic stem cells, which are the root cause of AML that must be eradicated for a complete cancer cure. In addition, the PU.1 target genes that are affected by PU.1 inhibition are not known, and the identification of these genes may identify biomarkers for any clinical translation of these inhibitors as well other potential drug targets. We will also use an exciting new technology, CLICK chemistry sequencing, to identify the specific binding location of the drug. This method uses a very slight modification of the drug to contain a tag that can be experimentally detected, allowing us to identify exactly where the drug is binding. Some drug binding sites may be strong binders and some may be weak binders, and we hypothesize that strong binders may represent locations that regulate genes important for the anti-leukemic effect of our PU.1 inhibitors. Our CLICK chemistry sequencing results will complement our gene expression analysis to identify the most important targets of PU.1 inhibition that mediates the anti-tumor effects of PU.1 inhibition. My goal is to establish PU.1 inhibition as a new AML therapy to improve the survival of patients with this disease.