Genomic interrogation of high-risk myeloid neoplasms to identify new therapies
Megan McNerney
MD PhDThe University of Chicago
Project Term: July 1, 2022 - June 30, 2027
The long-term goal of my research program is to improve the outcomes for patients with high-risk myeloid blood cancers, particularly those with loss of chromosome 7 or CUX1. We are tackling this question using an arsenal of innovative methods and tools, including mouse models, human cells and patient samples, and state-of-the-art technologies to examine the cancer cell genome. Accomplishing this work will reveal new treatments and strategies for preventing blood cancers from arising.
Billions of blood cells are produced every day. To accomplish this, blood stem cells must proliferate to give rise to the new daughter cells. Each time they divide, the cells must make an accurate copy of their DNA. Mistakes can occur in the process, however. Erros in the DNA can have fatal consequences, causing the stem cell to become immortal and not produce functioning blood cells. These immortal cells can become blood cancers, of which there are many different types. Our lab studies one such type, termed myeloid blood cancers, which occur in over 50,000 people every year in the U.S. alone. Some patients respond well to treatment, whereas others do not and are considered high-risk. The long-term goal of my research program is to improve the outcomes for patients with high-risk myeloid blood cancers. In half of the cancers of high-risk patients, the error the blood cells have acquired is loss of part or all of an entire chromosome, chromosome number 7. Also known as “-7”, this is a large mistake leading to the loss of nearly 5% of the genes in these cells. Although we have known of -7 for over forty years, we still do not have a clear understanding of which genes on chromosome 7 are important, and why. To this end, our research focuses on understanding -7, to ultimately identify new treatment avenues. We are tackling this question using an arsenal of innovative methods and tools, including mouse models, human cells and patient samples, and state-of-the-art technologies to examine the cancer cell genome. We have identified one critical gene on chromosome 7, called CUX1. CUX1 is a master-regulator of the genome, and loss of this single gene is sufficient to cause blood cancer in mice, highlighting its importance. Ongoing studies in the lab are identifying why CUX1 is critical in blood cells, and how to use this information to find new therapies. We are also investigating whether other genes on chromosome 7 are cooperating and how. In addition, we are identifying what environmental exposures cause these mutant cells to grow. Accomplishing this work will reveal new treatments and strategies for preventing blood cancers from arising.