Sylvester Research Identifies Novel Vulnerability in Acute Leukemia Cells
Researchers at the NCI-designated Sylvester Comprehensive Cancer Center, working within several departments at the University of Miami Miller School of Medicine, have identified another critical component of the AML1-ETO multi-protein complex that could point the way to more effective therapies for acute myeloid leukemia (AML). AML1-ETO (AE) is a protein generated by a chromosomal translocation that is relatively common in AML, a very aggressive cancer that remains difficult to treat effectively.
“AML1-ETO is an important driver of leukemia initiation and maintenance,” said Sylvester Director Stephen D. Nimer, M.D., who led this research, which was published Oct. 29 in Nature Communications. “AML1-ETO has been difficult to directly target. It binds to DNA tightly, an interaction that is very difficult to block.
“We have been studying AML1-ETO for decades, in order to develop a targeted therapy for AML,” he said. “We have focused on enzymes that bind to AML1-ETO, because enzyme inhibitors are easier to generate and test. We have also focused on critical proteins that interact with AML1-ETO to cause leukemia. Once we learn how two proteins interact, we can block the interaction, like preventing a key from fitting into a lock. But you have to know which protein-protein interactions are critical to the growth of the cancer, because it is only those interactions that are worth targeting. Compounds that can disrupt those interactions may be useful drugs that can be used to treat leukemia and possibly other cancers.”
The Nimer lab has worked with researchers at Sylvester, and researchers from Shanghai, for many years to identify all of the proteins that interact with AE, and then test in model systems which interacting proteins are important to the leukemia. They demonstrated a critical connection between AE, the methyltransferase enzyme p300, and a protein known as TAF1 or TAFII250. They have elucidated that for TAF1 to bind AE, AE must be acetylated by p300. Binding of TAF1 to AE allows it to activate genes important for leukemogenesis; in their study they show that blocking the binding of TAF1 to AE, or reducing the level of TAF1 in cells that contain AE, blocks the growth of acute leukemia cells.
From a therapeutic standpoint, this could be a big deal, as keeping TAF1, and other critical interacting proteins, away from AE could mitigate its ability to influence gene expression and drive AML. In this instance, the region of TAF1 required for binding to AE was identified as its bromodomain, a common amino acid motif that governs protein/protein interactions. “TAF1 recognizes AE through its bromodomain, which is very promising,” said Dr. Nimer. “There are numerous bromodomain inhibitors that are now being tested in cancer patients.”
In the published study, the team tested a bromodomain inhibitor against TAF1, and found that it blocked TAF1-AE binding and prolonged survival in animal models of leukemia. Although the inhibitor used is not suitable for patients, these results suggest that more advanced molecules could be used therapeutically.
“By understanding how leukemia arises, we are going to identify vulnerabilities that are created by the very genes that cause the cancer,” said Dr. Nimer. “Clinically, AML is one of the absolute worst cancers. We have built great teams at Sylvester, who are working together to find new cures for this disease.”