What if cancer treatments could zero in on the bad cells—and leave the good ones alone? That’s a question scientists at UT Southwestern are asking. And according to the Dallas-based medical center, that goal may be closer to reality—thanks to research that uncovered how a little-known protein is helping some blood cancers survive.

The protein, called midnolin, isn’t a hero in this story. It plays a critical role in helping malignant B cells stay alive in cancers like leukemia, lymphoma, and multiple myeloma. But by figuring out its structure using cryo-electron microscopy, UTSW researchers say they’ve opened the door to new therapies that could target midnolin—and potentially shut it down—without harming healthy cells.

The work could lead to new pharmaceuticals that avoid the serious side effects of current therapies. In lab models, turning off midnolin wiped out up to 92% of cancer cells—with minimal impact on healthy ones, according to a UT Southwestern post. 

By mapping the protein’s structure, the team got a better look at how midnolin helps cancerous cells clear out cellular junk, a job typically handled through a well-known process. But midnolin seems to take a different route. 

“This protein helps cells dispose of other unneeded proteins in a way that’s different from the classical mechanism we’re used to seeing,” said Nagesh Peddada, a PhD who co-led the study at UT Southwestern.

That twist could reveal new ways to disrupt the disease without affecting healthy cells.

Nagesh Peddada, Ph.D. (left), assistant professor in the Center for the Genetics of Host Defense and of Immunology at UT Southwestern, and Bruce Beutler, M.D., director of the Center for the Genetics of Host Defense and Professor of Immunology and Internal Medicine [Photos: UTSW]

Co-leader a pioneering Nobel Prize winner

Peddada co-led the study with immunologist Dr. Bruce Beutler. The research was funded by grants from the National Institutes of Health and The Welch Foundation.

Dr. Beutler shared the 2011 Nobel Prize in Physiology or Medicine for his discovery of an important family of receptors found on immune cells, UTSW said. The Nobel Prize winner has long used mutagenesis, a method for introducing mutations into the genes of animal models, as a key approach for discovering the function of genes.

According to UTSW, the Beutler Lab recently pioneered a method called automated meiotic mapping (AMM) that links abnormal traits in mutant mice to the mutations that cause them, thereby identifying genes needed to maintain a normal physiologic state.

Using genetic tools to protect against cancer

Combining those tools, Beutler and his colleagues reported last year that mutations in Midn, the gene that produces midnolin, protected mice that are genetically predisposed to developing B-cell leukemias and lymphomas. UTSW said that B cells — critical components of the adaptive immune system — divide out of control in these types of cancer.

Using genetic tricks to eliminate or reduce midnolin production significantly extended the affected animals’ lifespans by preventing them from developing those diseases, per UTSW.

More experiments revealed that midnolin’s role in B cells is to ferry proteins to proteasomes, cellular organelles that degrade proteins that are damaged or no longer useful to the cell.

Researchers said that midnolin also stimulates proteasome activity, increasing the rate at which damaged proteins are removed from cells. Almost all proteins routed to proteasomes are tagged for disposal by another protein called ubiquitin.

Proteins carried by midnolin aren’t tagged with ubiquitin, Peddada said. How midnolin functions without ubiquitin’s help has been unclear.

Key equipment and contributors

UTSW’s Cryo-Electron Microscopy Facility enabled the researchers to obtain three-dimensional images of midnolin bound to proteasomes at nearly atomic-level resolution, the medical center said. The images showed key portions of midnolin that are critical for its partnership with proteasomes. UTSW said that one of these portions has a shape similar to ubiquitin that allows midnolin to open the same gateway in proteasomes that proteins must cross for their disposal.

Other UTSW researchers who contributed to this study include Xiaochen Bai, Ph.D., associate professor of Biophysics and Cell Biology; Xue Zhong, Ph.D., Jin Huk Choi, Ph.D., and Eva Maria Y. Moresco, Ph.D., assistant professors in the Center for the Genetics of Host Defense and of Immunology; Yan Yin, Ph.D., Research Scientist; Danielle Renee Lazaro, B.S., Research Technician II; Jianhui Wang, M.S., senior research scientist; and Stephen Lyon, M.A., computational research scientist.

Quincy Preston contributed to this post.

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