Deciphering mutually exclusive T-ALL and neurodevelopmental mutations in the ARD domain of the ZMIZ1 coactivator

Dr. Mark Chiang, M.D., Ph.D. – The Regents of the University of Michigan, Ann Arbor, MI

There is an urgent need to find new drugs for ETP leukemia because the usual ones don’t work. It is also a large subtype, comprising 20% of pediatric T-ALL patients. Little is known about ETP cancer since it was recently defined. When scientists try to find a cure for a cancer, a popular idea is to find a drug that blocks a specific genetic mutation. But this approach would be inefficient for ETP leukemia because each mutation is rare. To overcome this challenge, our vision is to target the cell state that is shared by all ETP cancers rather than a specific mutation. What gives an ETP cell its state of "ETP-ness"? The answer is a genetic circuit inside cells that we call the "ETP gene network". This network turns on stem cell genes. Recently, my lab reported that the ZMIZ1 protein activates this network. We examined a part of ZMIZ1 called the ARD that is mutated in T-ALL and a neurodevelopmental disorder. Our initial work modeling these mutations suggests that the mutant ARD protects ZMIZ1 from being degraded and helps it rope together several control centers in the ETP gene network to construct "super control centers" with extraordinarily high activity. In our B+ project, we will learn how these mutations protect ZMIZ1 in order to find ways to overcome this protection and degrade ZMIZ1. Importantly, ZMIZ1 is not essential for health. Therefore, drugs that degrade ZMIZ1 might be a new kind of therapy that avoids the toxic effects of chemotherapy and help all ETP patients.