Targeting protein has potential to treat leukemia, lymphoma
UTSW study shows that modifying, deleting, or degrading a protein called ZFP574 reduces division of malignant B cells in lab
DALLAS – Aug. 01, 2024 – Targeting a protein called ZFP574 suppressed leukemia in a mouse model of the disease, UT Southwestern Medical Center researchers showed in a new study. Their findings, published in PNAS (Proceedings of the National Academy of Sciences), could lead to new treatments for leukemias and lymphomas in cancer patients.
“Effective treatments exist for B-cell malignancies such as leukemias and lymphomas. But in a significant portion of patients, these treatments stop working and their disease recurs, leaving them with no viable treatment options. Targeting ZFP574 could eventually fill an unmet need, either as a primary or backup therapeutic,” said Jin Huk Choi, Ph.D., Assistant Professor in the Center for the Genetics of Host Defense and of Immunology.
Dr. Choi co-led the study with Bruce Beutler, M.D., Director of the Center for the Genetics of Host Defense and Professor of Immunology and Internal Medicine. The study’s first author is Xue Zhong, Ph.D., Instructor in the Center for the Genetics of Host Defense and of Immunology. Drs. Choi and Zhong are former postdoctoral researchers in the Beutler Lab.
Dr. Beutler shared the 2011 Nobel Prize in Physiology or Medicine for his discovery of an important family of pathogen sensors known as Toll-like receptors found on immune cells. He has long used mutagenesis – introducing mutations into the genes of animal models through exposure to a chemical called N-ethyl-N-nitrosourea (ENU) – as a key tool for discovering the function of genes. Recently, the Beutler Lab pioneered a method known as automated meiotic mapping (AMM) that traces unusual features in mutant mice, thereby identifying genes needed to maintain the normal physiologic state.
Combining these techniques in mice, Drs. Choi, Beutler, and Zhong and their colleagues searched for genes that might play important roles in the development of B cells. These are white blood cells that fight infections as part of the adaptive immune system. The team quickly homed in on a gene called Zfp574, which produces the ZFP574 protein that previously was not known to have any function in immunity.
Experiments showed that mutating this gene in embryos prevented development, suggesting that it’s essential to life. When the researchers used a genetic technique to control its activity in healthy adult mice, they found that switching Zfp574 off dramatically decreased the number of B cells, making the animals immunodeficient. Further experiments showed that ZFP574 appears to be responsible for controlling an important part of the cell cycle, the process by which cells multiply.
Because many cancer drugs work by inhibiting the cell cycle – preventing malignant cells from their characteristic rapid division – the scientists wondered whether inhibiting ZFP574 could be a way to treat B-cell cancers such as leukemia and lymphoma. Tests in a mouse model of leukemia showed that mutating or deleting Zfp574, or using pharmaceuticals to degrade ZFP574, reduced the amount of malignant B cells by as much as 92%. Normal B cells were largely spared due to their significantly slower cell division, Dr. Choi explained.
“Not only leukemias and lymphomas, but perhaps many cancers will respond to inhibition of ZFP574,” said Dr. Beutler, a member of the Cellular Networks in Cancer Research Program in the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern. “The use of a random germline mutagen to discover a new and essential component of the cell cycle – despite the fact that the cell cycle has been intensively studied for many years – suggests there may still be plenty of new targets to exploit in controlling cancer cell proliferation.”
Future studies will focus on ZFP574’s atomic structure and how it controls B-cell cycling, knowledge that could help pharmaceutical companies eventually develop drugs targeting ZFP574 to treat leukemias, lymphomas, and potentially other cancers.
Dr. Beutler, a Regental Professor, holds the Raymond and Ellen Willie Distinguished Chair in Cancer Research, in Honor of Laverne and Raymond Willie, Sr.
Other UTSW researchers who contributed to this study are James J. Moresco, Ph.D., Assistant Professor in the Center for the Genetics of Host Defense and of Biophysics; Jeffrey A. SoRelle, M.D., Assistant Professor of Pathology and Pediatrics; Eva Marie Y. Moresco, Ph.D., Assistant Professor in the Center for the Genetics of Host Defense and of Immunology; Ran Song, Ph.D., Mylinh T. Nguyen, M.S., and Jianhui Wang, M.S., Senior Research Scientists; Chun Hui Bu, Ph.D., Computational Biologist; and Yiao Jiang, Ph.D., postdoctoral researcher.
This research was funded by the National Institutes of Health (AI125581 and CA258602).
About UT Southwestern Medical Center
UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 21 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,200 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 120,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5 million outpatient visits a year.