Selective Epigenetic Regulation of Notch1 in T-cell Acute Lymphoblastic Leukemia
More children die from acute lymphoblastic leukemia (ALL) than from any other cancer. NOTCH1 was found to be the most frequent cancer-causing gene in T-ALL. However, in clinical trials anti-NOTCH drugs had too much toxicity and even promoted cancers. The reason for these side effects is that Notch is an important protein that keeps normal tissues healthy. How can we knock out Notch in cancer, but preserve Notch in normal cells? We believe that the answer may be two proteins called Zmiz1 and Ets1.
We found that Zmiz1 sticks to Notch and triggers its cancer-causing functions but not its normal functions. When we turned off Zmiz1 in a mouse with leukemia, the tumors shrank without damaging normal tissues or causing new cancers. We think that Zmiz1 does this by connecting Notch to other cancer-causing proteins, in particular Ets1.
The first part of our proposal tests the theory that Ets1 sits on DNA, pulls in Zmiz1 and other important cancer proteins and attaches them to the nearby Notch protein, which triggers the cancer-causing functions of Notch. The second part tests the effect of blocking Ets1 in normal and leukemia cells in order to learn whether anti-ETS1 drugs would be safe and effective. These studies will help us develop anti-NOTCH cancer therapy without the unacceptable consequences of blocking all Notch functions. We test human samples to ensure that our results are relevant to humans. As a physician-scientist who actively takes care of leukemia patients, I am well-positioned to efficiently deliver new therapies.