Exploiting the Context-dependent Interaction of Notch1 and Ets1 in T-ALL

Background

Notch was found to be the most frequent cancer-causing gene in T cell acute lymphoblastic leukemia (T-ALL). This discovery raised hopes for anti-Notch drugs. However, these drugs had too much toxicity, like diarrhea and even promoted cancers. The reason for these side effects is that Notch is very important for keeping normal tissues healthy. How can we knock out Notch in cancer, but preserve Notch in normal cells? We believe that the answer may be proteins called cofactors that stick to Notch. We've noticed that some cofactors tell Notch to drive cancer. Other cofactors tell Notch to keep organs healthy. Our idea is that inhibiting the specific cofactors that tell Notch to drive cancer, but not the other cofactors, could combat Notch without intolerable side effects. In support of our idea, we recently discovered that the cofactor Zmiz1 sticks to Notch and triggers its cancer-causing functions but not its normal functions. When we removed Zmiz1 from a leukemic mouse, the tumors shrank without damaging normal tissues or causing new cancers. This year, we learned that another cofactor, Ets1, also sticks to Notch1. 

Project Goal

For the POST project, we propose to map the surfaces where the Ets1, Zmiz1 and Notch1 proteins stick together. We will also learn whether separating these proteins disrupts the cancer-causing commands that Ets1 sends to Notch1. We will test human samples to ensure that our results are relevant to human cancer. Thus, these studies will help us develop anti-Notch cancer therapy without the intolerable side effects of total Notch blockade.